Diaryl urea derivatives useful for the treatment of protein kinase dependent diseases

ABSTRACT

The invention relates to the use of diaryl urea derivatives in the treatment of protein kinase dependent diseases or for the manufacture of pharmaceutical compositions for use in the treatment of said diseases, methods of use of diaryl urea derivatives in the treatment of said diseases, pharmaceutical preparations comprising diaryl urea derivatives for the treatment of said diseases, diaryl urea derivatives for use in the treatment of said diseases, novel diaryl urea derivatives, pharmaceutical preparations comprising these novel diaryl urea derivatives, processes for the manufacture of the novel diaryl urea derivatives, the use or methods of use of the novel diaryl urea derivatives as mentioned above, and/or these novel diaryl urea derivatives for use in the treatment of the animal or human body.

SUMMARY OF THE INVENTION

The invention relates to the use of diaryl urea derivatives in thetreatment of protein kinase dependent diseases or for the manufacture ofpharmaceutical compositions for use in the treatment of said diseases,methods of use of diaryl urea derivatives in the treatment of saiddiseases, pharmaceutical preparations comprising diaryl urea derivativesfor the treatment of said diseases, diaryl urea derivatives for use inthe treatment of said diseases, novel diaryl urea derivatives,pharmaceutical preparations comprising these novel diaryl ureaderivatives, processes for the manufacture of the novel diaryl ureaderivatives, the use or methods of use of the novel diaryl ureaderivatives as mentioned above, and/or these novel diaryl ureaderivatives for use in the treatment of the animal or human body.

BACKGROUND OF THE INVENTION

Protein kinases (PKs) are enzymes which catalyze the phosphorylation ofspecific serine, threonine or tyrosine residues in cellular proteins.These post-translational modifications of substrate proteins act asmolecular switch regulating cell proliferation, activation and/ordifferentiation. Aberrant or excessive PK activity has been observed inmany disease states including benign and malignant proliferativedisorders. In many cases, it has been possible to treat diseases invitro and in many cases in vivo, such as proliferative disorders, bymaking use of PK inhibitors.

In view of the large number of protein kinase inhibitors and themultitude of proliferative and other PK-related diseases, there is anever-existing need to provide novel classes of compounds that are usefulas PK inhibitors and thus in the treatment of these PTK relateddiseases. What is required are new classes of pharmaceuticallyadvantageous PK inhibiting compounds.

GENERAL DESCRIPTION OF THE INVENTION

It has now been found that various compounds of the diaryl ureaderivative class show inhibition of a number of protein tyrosinekinases. Among the advantages, a good bioavailability and, especiallywhere substituents at the ring with A and A′ in formula I or I* givenbelow are present, lower accessibility to metabolism are to bementioned. The compounds of formula I or I*, described below in moredetail, especially show inhibition of one or more of the followingprotein tyrosine kinases: c-Abl, Bcr-Abl, the receptor tyrosine kinasesFlt3, VEGF-R or c-Kit, as well as combinations of tow or more of these;in the case of novel diaryl urea derivatives according to the invention,the compounds are appropriate for the inhibition of these and/or otherprotein tyrosine kinases, especially those mentioned above and/or, inaddition, the non-receptor tyrosine kinase Raf, and/or for theinhibition of mutants of these enzymes, especially of Bcr-Abl, forexample the Glu255→Lysine mutant. In view of these activities, thecompounds can be used for the treatment of diseases related toespecially aberrant or excessive activity of such types of kinases,especially those mentioned.

DETAILED DESCRIPTION OF THE INVENTION

The invention especially relates to the use of diaryl urea derivativesthat are compounds of the formula I

wherein G is either not present, lower alkylene or C₃-C₅cycloalkyleneand Z is a radical of the formula Ia

or G is not present and Z is a radical of the formula Ib

A is CH, N or N→O and A′ is N or N→O, with the proviso that not morethan one of A and A′ can be N→O;

n is 1 or 2;

m is 0, 1 or 2;

p is 0, 2or 3;

r is 0 to 5;

X is NR if p is 0, wherein R is hydrogen or an organic moiety, or if pis 2 or 3, X is nitrogen which together with (CH₂)_(p) and the bondsrepresented in dotted (interrupted) lines (including the atoms to whichthey are bound) forms a ring, or

X is CHK wherein K is lower alkyl or hydrogen and p is zero,

with the proviso that the bonds represented in dotted lines, if p iszero, are absent;

Y₁ is O, S or CH₂;

Y₂ is O, S or NH;

with the proviso that (Y₁)_(n)—(Y₂), does not include O—O, S—S, NH—O,NH—S or S—O groups; each of R₁, R₂, R₃ and R₅, independently of theothers, is hydrogen or an inorganic or organic moiety or any two of themtogether form a lower alkylene-dioxy bridge bound via the oxygen atoms,and the remaining one of these moieties is hydrogen or an inorganic ororganic moiety;

and R₄ (if present, that is, if r is not zero) is an inorganic ororganic moiety;

or a tautomer thereof;

or a pharmaceutically acceptable salt thereof;

In the treatment of protein kinase (especially tyrosine protein kinase)dependent diseases or for the manufacture of pharmaceutical compositionsfor use in the treatment of said diseases, methods of use of diaryl ureaderivatives in the treatment of said diseases, pharmaceuticalpreparations comprising diaryl urea derivatives for the treatment ofsaid diseases, diaryl urea derivatives for use in the treatment of saiddiseases.

The invention further also relates to the use or diaryl urea derivativesas described above, wherein the diaryl urea derivative is a compound ofthe formula I*

wherein A, A′, n, m, p, r, X, Y₁, Y₂ and R₁—R₅ have the meanings asdefined above for a compound of formula I;

or a tautomer thereof;

or pharmaceutically acceptable salts thereof.

The invention especially relates to novel diaryl urea derivatives,especially a compound selected from the compounds of the formula I or I*in the Examples, or a salt thereof,

especially

(i) the novel compounds of the formula I wherein

A is CH, N or N→O and A′ is N or N→O, with the proviso that not morethan one of A and A′ can be N→O;

n is 1 or 2;

m is 0, 1 or 2;

p is 0, 2 or 3;

r is 1 to 5;

X is NR if p is 0, wherein R is hydrogen or an organic moiety, or if pis 2 or 3, X is nitrogen which together with (CH₂)_(p) and the bondsrepresented in dotted (interrupted) lines (including the atoms to whichthey are bound) forms a ring,

with the proviso that if X is NH, each of R₄, independently of theothers if r>1, is a moiety as defined above under formula I but notbound to the rest of formula I via a —C(═O)—, —C(NR)— or —S(O₂)— bridge,or

X is CHK wherein K is lower alkyl or hydrogen and p is zero,

with the proviso that the bonds represented in dotted lines, if p iszero, are absent;

Y₁ is O, S or CH₂;

Y₂ is O, S or NH;

with the proviso that (Y₁)_(n)—(Y₂)_(m) does not include O—O, S—S, NH—O,NH—S or S—O groups;

each of R₁, R₂, R₃ and R₅, independently of the others, is hydrogen oran inorganic or organic moiety or any two of R₁, R₂ and R₃ together forma lower alkylene-dioxy bridge bound via the oxygen atoms, and theremaining one of these moieties is hydrogen or an inorganic or organicmoiety, with the proviso that if G is not present and Z is a radical ofthe formula Ia, R₁, R₂ and R₃ cannot all be hydrogen and with thefurther proviso that if one of R₁, R₂ and R₃ is halo or loweralkyl-sulfonyl, the other two cannot both be hydrogen; R₄ is aninorganic or organic moiety, with the proviso that if n is 1, m is 0, pis 0, r is 1, X is NH, Y₁ is O, G is not present and Z is a radical ofthe formula Ia, R₄, together with the benzene ring containing A and A′,does not form methylpyridinyl, 2-hydroxy-pyridin-4-yl or1-H-2-oxo-1,2-dihydropyridin-4-yl; and

G and Z have the meanings given above under formula I;

or a tautomer thereof;

or pharmaceutically acceptable salts thereof; and

(ii) the novel compounds of the formula I* wherein

A is CH, N or N→O and A′ is N or N→O, with the proviso that not morethan one of A and A′ can be N→O;

n is 1;

m is 0;

p is 0, 2 or 3;

r is 1;

X is NR if p is 0, wherein R is hydrogen or lower alkyl, or if p is 2 or3, X is nitrogen which together with (CH₂)_(p) and the bonds representedin dotted (interrupted) lines (including the atoms to which they arebound) forms a ring, or

X is CH₂ and p is zero,

with the proviso that the bonds represented in dotted lines, if p iszero, are absent;

Y₁ is O or CH₂;

each of R₁, R₂ and R₃ independently of the others, is hydrogen, loweralkyl, halo, especially bromo or chloro, halo-lower alkyl, especiallytrifluoromethyl, lower alkoxy, especially methoxy, halo-lower alkoxy,especially 2,2,2-trifluoroethoxy, phenyl, piperidyl, especiallypiperidin-1-yl, piperazinyl, especially piperazin-1-yl, morpholinyl,especially morpholine, thiomorpholinyl, especially thiomorpholino, orany two of them together form a lower alkylene-dioxy bridge bound viathe oxygen atoms, and the remaining one of these moieties is hydrogen orone of the moieties mentioned, with the proviso that R₁, R₂ and R₃cannot all be hydrogen and with the further proviso that if one of R₁,R₂ and R₃ is halo, the other two cannot both be hydrogen;

R₄ is lower alkoxy, especially methoxy, lower alkanoylamino, especiallyacetylamino, hydroxyphenylamino, especially p-hydroxyphenylamino,amino-lower alkyl-oxyphenyl-amino, especially4-[(2-aminoethyl)-oxyphenyl]-amino, sulfamoylphenylamino, especially4-sulfamoylphenylamino, carbamoylphenylamino, especially4-carbamoylphenylamino, [N-(hydroxy-lower alkyl)-carbamoyl]-phenylamino,especially [N-(2-hydroxyethyl)-carbamoyl]-phenylamino, or halo,especially chloro; and

R₅ is hydrogen, lower alkyl or halo, especially hydrogen;

or a tautomer thereof;

or pharmaceutically acceptable salts thereof;

to pharmaceutical preparations comprising these novel diaryl ureaderivatives or pharmaceutically acceptable salts thereof, processes forthe manufacture of the novel diaryl urea derivatives or pharmaceuticallyacceptable salts thereof, the use or methods of use of the novel diarylurea derivatives or pharmaceutically acceptable salts thereof asmentioned above, and/or these novel diaryl urea derivatives orpharmaceutically acceptable salts thereof for use in the treatment ofthe animal or human body.

The general terms used hereinbefore and hereinafter preferably have,within this disclosure, the following meanings, unless otherwiseindicated:

The prefix “lower” denotes a radical having 1 up to and including amaximum of 7, especially 1 up to and including a maximum of 4 carbonatoms, the radicals in question being either linear or branched withsingle or multiple branching. Lower alkyl, for example, is methyl,ethyl, n-propyl, sec-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, n-hexyl or n-heptyl.

Where the plural form is used for compounds, salts, pharmaceuticalpreparations, diseases and the like, this is intended to mean also asingle compound, salt, or the like.

Halo(geno) is preferably iodo, bromo, chloro or fluoro, especiallyfluoro, chloro or bromo.

In view of the close relationship between the diaryl urea derivatives infree form and in the form of their salts, including those salts that canbe used as intermediates, for example in the purification oridentification of the novel compounds, tautomers or tautomeric mixturesand their salts, any reference hereinbefore and hereinafter to thesecompounds, especially the compounds of the formula I or I*, is to beunderstood as referring also to the corresponding tautomers of thesecompounds, especially of compounds of the formula I or I*, tautomericmixtures of these compounds, especially of compounds of the formula I orI*, or salts of any of these, as appropriate and expedient and if notmentioned otherwise. Tautomers can, e.g., be present in cases whereamino or hydroxy, each with a least one bound hydrogen, are bound tocarbon atoms that are bound to adjacent atoms by double bonds (e.g.keto-enol or imine-enamine tautoemerism). Preferred tautomers are thepyridin-on-yl or pyrimidin-on-yl forms of compounds wherein R₄ ishydroxy and the other moieties are defined as for compounds of theformula I or I*, respectively.

Where {a compound . . . , a tautomer thereof; or a salt thereof” or thelike is mentioned, this means “a compound . . . , a tautomer thereof, ora salt of the compound or the tautomer”.

Any asymmetric carbon atom may be present in the (R)—, (S)— or(R,S)-configuration, preferably in the (R)— or (S)-configuration.Substituents at a ring at atoms with saturated bonds may, if possible,be present in cis-(=Z-) or trans (=E-) form. The compounds may thus bepresent as mixtures of isomers or preferably as pure isomers, preferablyas enantiomer-pure diastereomers or pure enantiomers.

Salts are preferably the pharmaceutically acceptable salts of the diarylurea derivatives, especially of compounds of the formula I or I* if theyare carrying salt-forming groups.

Salt-forming groups are groups or radicals having basic or acidicproperties. Compounds having at least one basic group or at least onebasic radical, for example amino, a secondary amino group not forming apeptide bond or a pyridyl radical, may form acid addition salts, forexample with inorganic acids, such as hydrochloric acid, sulfuric acidor a phosphoric acid, or with suitable organic carboxylic or sulfonicacids, for example aliphatic mono- or di-carboxylic acids, such astrifluoroacetic acid, acetic acid, propionic acid, glycolic acid,succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malicacid, tartaric acid, citric acid or oxalic acid, or amino acids such asarginine or lysine, aromatic carboxylic acids, such as benzoic acid,2-phenoxy-benzoic acid, 2-acetoxy-benzoic acid, salicylic acid,4-aminosalicylic acid, aromatic-aliphatic carboxylic acids, such asmandelic acid or cinnamic acid, heteroaromatic carboxylic acids, such asnicotinic acid or isonicotinic acid, aliphatic sulfonic acids, such asmethane-, ethane- or 2-hydroxyethanesulfonic acid, or aromatic sulfonicacids, for example benzene-, p-toluene- or naphthalene-2-sulfonic acid.When several basic groups are present mono- or poly-acid addition saltsmay be formed.

Compounds having acidic groups, a carboxy group or a phenolic hydroxygroup, may form metal or ammonium salts, such as alkali metal oralkaline earth metal salts, for example sodium, potassium, magnesium orcalcium salts, or ammonium salts with ammonia or suitable organicamines, such as tertiary monoamines, for example triethylamine ortri-(2-hydroxy-ethyl)-amine, or heterocyclic bases, for exampleN-ethyl-piperidine or N,N′-dimethylpiperazine. Mixtures of salts arepossible.

Compounds having both acidic and basic groups can form internal salts.

For the purposes of isolation or purification, as well as in the case ofcompounds that are used further as intermediates, it is also possible touse pharmaceutically unacceptable salts, e.g. the picrates. Onlypharmaceutically acceptable, non-toxic salts may be used for therapeuticpurposes, however, and those salts are therefore preferred.

An organic moiety R is preferably unsubstituted or substituted alkyl,unsubstituted or substituted alkenyl, unsubstituted or substitutedalkynyl, unsubstituted or substituted aryl, unsubstituted or substitutedheterocyclyl, unsubstituted or substituted cycloalkyl or unsubstitutedor substituted cycloalkenyl; preferred is unsubstituted alkyl.

“Substituted”, whereever used for a moiety, means that one or morehydrogen atoms in the respective moiety, especially up to 5, moreespecially up to three, of the hydrogen atoms are replaced independentlyof each other by the corresponding number of substituents whichpreferably are independently selected from the group consisting of loweralkyl, for example methyl, ethyl or propyl, halo-lower alkyl, forexample trifluoromethyl, C₆-C₁₆-aryl, especially phenyl or naphthyl(where C₆C₁₆-aryl, especially phenyl or napthyl, is unsubstituted orsubstituted by one or more, especially up to three moieties selectedfrom halogen, carboxy, lower alkoxycarbonyl, hydroxy, lower alkoxy,phenyl-lower alkoxy, lower alkanoyloxy, lower alkanoyl, amino, N-loweralkylamino, N,N-di-lower alkylamino, N-phenyl-lower alkylamino,N,N-bis(phenyl-lower alkyl)amino, lower alkanoylamino, halo, halo-loweralkyl, e.g. trifluoro-methyl, sulfo, sulfamoyl, carbamoyl, N-loweralkyl-carbamoyl, N-(hydroxy-lower alkyl)-carbamoyl, such asN-(2-hydroxyethyl)-carbamoyl, cyano, cyano-lower alkyl and nitro),C₃-C₁₀-cycloalkyl, especially cyclopropyl or cyclohexyl,hydroxy-C₃-C₈-cycloalkyl, such as hydroxy-cyclohexyl, heterocyclyl with5 or 6 ring atoms and 1 to 3 ring heteroatoms selected from O, N and S,especially piperidinyl, especially piperidin-1-yl, piperazinyl,especially piperazin-1-yl, morpholinyl, especially morpholin-1-yl,hydroxy, lower alkoxy, for example methoxy, halo-lower alkoxy,especially 2,2,2-trifluoroethoxy, phenyl-lower alkoxy, amino-loweralkoxy, such as 2-eminoethoxy; lower alkanoyloxy, hydroxy-lower alkyl,such as hydroxymethyl or 2-hydroxyethyl, amino, N-lower alkylamino,N,N-di-lower alkylamino, N-phenyl-lower alkylamino, N,N-bis(phenyl-loweralkyl)amino, lower alkanoylamino, especially acetylamino, benzoylamino,carbamoyl-lower alkoxy, N-lower alkylcarbamoyl-lower alkoxy orN,N-di-lower alkyl-carbamoyl-lower alkoxy, amidino, N-hydroxy-amidino,guanidino, amino-lower alkyl, such as aminomethyl or 2-aminoethyl,amidino-lower alkyl, such as 2-amidinoethyl, N-hydroxyamidino-loweralkyl, such as N-hydroxy-amidino-methyl or -2-ethyl, halogen, forexample fluoro, chloro, bromo or iodo, carboxy, lower alkoxycarbonyl,phenyl-, naphthyl- or fluorenyl-lower alkoxycarbonyl, such asbenzyloxycarbonyl, lower alkanoyl, sulfo, lower alkanesulfonyl, forexample methanesulfonyl (CH₃—S(O)₂—), phosphono (—P(═O)(OH)₂),hydroxy-lower alkoxy phosphoryl or di-lower alkoxyphosphoryl, carbamoyl,mono- or di-lower alkylcarbamoyl, mono- or di-(hydroxy-loweralkyl)-carbamoyl, sulfamoyl, mono- or di-lower alkylaminosulfonyl,nitro, cyano-lower alkyl, such as cyanomethyl, and cyano. It goeswithout saying that substitutents are only at positions where they arechemically possible, the person skilled in the art being able to decide(either experimentally or theoretically) without inappropriate effortwhich substitutions are possible and which are not. For example, aminoor hydroxy groups with free hydrogen may be unstable if bound to carbonatoms with unsaturated (e.g. olefinic) bonds.

Alkyl preferably has up to 20, more preferably up to 12 carbon atoms andis linear or branched one or more times; preferred is lower alkyl,especially C₁-C₄-alkyl, in particular methyl, ethyl or n-propyl. Alkylis unsubstituted or substituted, preferably by one or more substituentsindependently selected from those mentioned above under “Substituted”.Unsubstituted alkyl, preferably lower alkyl, is especially preferred asan organic moiety R.

Among the moieties corresponding to substituted alkyl, hydroxy-loweralkyl, especially 2-hydroxyethyl, and/or halo-lower alkyl, especiallytrifluoromethyl or 2,2,2-trifluoroethyl, are especially preferred.

Alkenyl is preferably a moiety with one or more double bonds andpreferably has 2 to 20, more preferably up to 12, carbon atoms; it islinear or branched one or more times (as far as possible in view of thenumber of carbon atoms). Preferred is C₂-C₇-alkenyl, especiallyC₃-C₄-alkenyl, such as allyl or crotyl. Alkenyl can be unsubstituted orsubstituted, especially by one or more, more especially up to three, ofthe substituents mentioned above under “substituted”. Substituents suchas amino or hydroxy (with free dissociable hydrogen) preferably are notbound to carbon atoms that participate at a double bond, and also othersubtituents that are not sufficiently stable are preferably excluded.Unsubstituted alkenyl, in particular C₂-C₇-alkenyl, is preferred.

Alkynyl is preferably a moiety with one or more triple bonds andpreferably has 2 to 20, more preferably up to 12, carbon atoms; it islinear of branched one or more times (as far as possible in view of thenumber of carbon atoms). Preferred is C₂-C₇-alkynyl, especiallyC₃-C₄-alkynyl, such as ethinyl or propin-2-yl. Alkynyl can beunsubstituted or substituted, especially by one or more, more especiallyup to three, of the substituents mentioned above under “substituted”.Substituents such as amino or hydroxy (with free dissociable hydrogen)preferably are not bound to carbon atoms that participate at a triplebond, and also other subtituents that are not sufficiently stable arepreferably excluded. Unsubstituted alkynyl, in particular C₂C₇-alkynyl,is preferred.

Aryl preferably has a ring system of not more than 16 carbon atoms, ispreferably mono-, bi- or tric-cyclic, and is unsubstituted orsubstituted preferably as defined above under “Substituted”. Preferably,aryl is selected from phenyl, naphthyl, indenyl, azulenyl and anthryl,and is preferably in each case unsubstituted or lower alkyl, especiallymethyl, ethyl or n-propyl, halo (especially fluoro, chloro, bromo oriodo), halo-lower alkyl (especially trifluoromethyl), hydroxy, loweralkoxy (especially methoxy), halo-lower alkoxy (especially2,2,2-trifluoroethoxy), amino-lower alkoxy (especially 2-amino-ethoxy),lower alkyl (especially methyl or ethyl) carbamoyl, N-(hydroxy-loweralkyl)-carbamoyl (especially N-(2-hydroxyethyl)-carbamoyl) and/orsulfamoyl-substituted aryl, especially a corresponding substituted orunsubstituted phenyl.

Heterocyclyl is preferably a heterocyclic radical that is unsaturated,saturated or partially saturated in the bonding ring and is preferably amonocyclic or in a broader aspect of the invention bicyclic or tricyclicring; has 3 to 24, more preferably 4 to 16 ring atoms; wherein at leastin the ring bonding to the radical of the molecule of formula I or I*one or more, preferably one to four, especially one or two carbon ringatoms are replaced by a heteroatom selected from the group consisting ofnitrogen, oxygen and sulfur, the bonding ring preferably having 4 to 12,especially 5 to 7 ring atoms; heteroaryl being unsubstituted orsubstituted by one or more, especially 1 to 3, substitutentsindependently selected from the group consisting of the substituentsdefined above under “Substituted”; especially being a heteroaryl radicalselected from the group consisting of oxiranyl, azirinyl,1,2-oxathiolanyl, imidazolyl, thienyl, furyl, tetrahydrofuryl, pyranyl,thiopyranyl, thianthrenyl, isobenzofuranyl, benzofuranyl, chromenyl,2H-pyrrolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl,imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl,pyranyol, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl,pyridyl, pyrazinyl, pyrimidinyl, piperidyl, especially piperidin-1-yl,piperazinyl, especially piperazin-1-yl, pyridazinyl, morpholinyl,especially morpholino, thiomorpholinyl, especially thiomorpholino,indolizinyl, isoindolyl, 3H-indolyl, indolyl, benzimidazolyl, cumaryl,indazolyl, triazolyl, tetrazolyl, purinyl, 4H-quinolizinyl, isoquinolyl,quinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl,octahydroisoquinolyl, benzofuranyl, dibenzofuranyl, benzothiophenyl,dibenzothiophenyl, phthalazinyl, naphthyridinyl, quinoxalyl,quinazolinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl,furazanyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromenyl,isochromanyl and chromanyl, each of these radicals being unsubstitutedor substituted by one to two radicals selected from the group consistingof lower alkyl, especially methyl or tert-butyl, lower alkoxy,especially methoxy, and halo, especially bromo or chloro. Unsubstitutedheterocyclyl, especially piperidyl, piperazinyl, thiomorpholino ormorpholino, is preferred.

Cycloalkyl is preferably C₃-C₁₀-cycloalkyl, especially cyclopropyl,dimethylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl,cycloalkyl being unsubstituted or substituted by one or more, especially1 to 3, substitutents independently selected from the group consistingof the substituents defined above under “Substituted”.

Cycloalkenyl is preferably C₅-C₁₀-cycloalkenyl, especiallycyclopentenyl, cyclohexenyl or cycloheptenyl, cycloalkenyl beingunsubstituted or substituted by one or more, especially 1 to 3,substitutents independently selected from the group consisting of thesubstituents defined above under “Substituted”.

An inorganic moiety is preferably halogen, hydroxy, amino, or nitro.

The bonds represented by dotted (interrupted) lines and binding(CH₂)_(p), are present if p is 2 or 3, or absent if p is zero.

An organic moiety is preferably unsubstituted or substituted alkyl,unsubstituted or substituted alkenyl, unsubstituted or substitutedalkynyl, unsubstituted or substituted unsubstituted or substituted aryl,unsubstituted or substituted heterocyclyl, unsubstituted or substitutedcycloalkyl or unsubstituted or substituted cycloalkenyl, unsubstitutedor substituted alkoxy, unsubstituted or substituted alkenyloxy,unsubstituted or substituted alkynyloxy, unsubstituted or substitutedaryloxy, unsubstituted or substituted heterocyclyloxy, unsubstituted orsubstituted cycloalkoxy or unsubstituted or substituted cycloalkenyloxy,or unsubstituted or substituted alkylamino, unsubstituted or substitutedalkenylamino, unsubstituted or substituted alkynylamino, unsubstitutedor substituted arylamino, unsubstituted or substitutedheterocyclylamino, unsubstituted or substituted cycloalkylamino orunsubstituted or substituted cycloalkenylamino.

An organic moiety is preferably alkyl, especially lower alkyl, such asmethyl, ethyl or propyl, halo-lower alkyl, such as trifluoromethyl,lower alkoxy, such as methoxy, halo-lower alkoxy, such as2,2,2-trifluoroethoxy, halo, such as chloro or bromo, phenyl,phenylamino, hydroxy-phenyl-amino, such as 4-hydroxyphenylamino,amino-lower alkyl-oxyphenylamino, such as[4-(2-aminoethyl)oxy]-phenyl-amino, carbamoylphenyl-amino, such as4-sulfamoyl-phenyl-amino, [N-(hydroxy-loweralkyl)-carbamoyl]-phenyl-amino, such as{N-[4-(2-hydroxyethyl)-carbamoyl]-phenyl)-amino, 5- or 6-memberedsaturated heterocyclyl with 1 or 2 heteroatoms selected from the groupconsisting of N, O and S, especially piperidyl, such as piperidin-1-yl,piperazinyl, such as piperazin-1-yl, morpholinyl, such as morpholino, orfurther thiomorpholinyl, such as thiomorpholino.

A basic organic moiety is a moiety selected from the definition of anorganic moiety as given herein and having basic (alkaline) properties.Preferably a basic organic moiety is piperidyl, especiallypiperidin-1-yl, piperidyl-lower alkyl, especially piperidin-1-ylmethyl,lower alkyl-piperazinyl, especially 4-methyl-piperazin-1-yl or4-ethyl-piperazin-1-yl, or lower alkyl-piperazinyl-lower alkyl,especially 4-methyl-piperazin-1-ylmethyl or4-ethyl-piperazin-1-ylmethyl.

If any two of R₁, R₂ and R₃ together form a lower alkylene-dioxy bridgebound via the oxygen atoms said bridge is preferably methylendioxy(O—CH₂—O) or ethylendioxy (O—CH₂—CH₂—O) bound via the oxygen atoms tovicinal carbon atoms, and the remaining one of these moieties ishydrogen or an inorganic or organic moiety as described above.

The term “treatment of tyrosine protein kinase dependent diseases”refers to the prophylactic or preferably therapeutic (includingpalliative and/or curing) treatment of said diseases, especially of thediseases mentioned below.

Where subsequently the term “USE” is mentioned, this includes any one ormore of the following embodiments of the invention, respectively: theuse in the treatment of (especially tyrosine) protein kinase dependentdiseases, the use for the manufacture of pharmaceutical compositions foruse in the treatment of said diseases, methods of use of diaryl ureaderivatives in the treatment of said diseases, pharmaceuticalpreparations comprising diaryl urea derivatives for the treatment ofsaid diseases, and diaryl urea derivatives for use in the treatment ofsaid diseases, as appropriate and expedient, if not stated otherwise. Inparticular, diseases to be treated and are thus preferred for USE of acompound of formula I or I* are selected from (especially tyrosine)protein kinase dependent (“dependent” meaning also “supported”, not only“solely dependent”) diseases mentioned below, especially correspondingproliferative diseases, more especially diseases that depend on ras,Abl, VEGF-receptor tyrosine kinase, Flt3, and/or Bcr-Abl activity,especially the diseases mentioned below under these specific tyrosineprotein kinases. Other kinases of interest include PDGF receptor, c-KITor EphB4 receptor.

In the novel diaryl urea derivatives of the formula I or I* in theexamples, or salts thereof, or the novel compounds of the formula I orI*, the proviso that if X is NH, each of R₄ independently of the others,is a substituent not bound to the rest of formula I or I*, respectively,via a —C(═O)—, —C(NR)— or —S(O₂)— bridge means that the substituents aresuch that they do not comprise any of these bridges. Preferred are thesubstituents given above and below as “organic moieties”.

The diaryl urea derivatives, especially the compounds of formula I orI*, have valuable pharmacological properties and are useful in thetreatment of protein kinase dependent diseases, especially of tyrosineprotein kinase dependent for example, as drugs to treat proliferativediseases.

The efficacy of the compounds of the invention as inhibitors of c-Ablprotein-tyrosine kinase activity can be demonstrated as follows:

An in vitro enzyme assay is performed in 96-well plates as a filterbinding assay as described by Geissler et al. in Cancer Res. 1992;52:4492-4498, with the following modifications. The His-tagged kinasedomain of c-Abl is cloned and expressed in the baculovirus/Sf9 system asdescribed by Bhat et al. in J. Biol. Chem. 1997; 272:16170-16175. Aprotein of 37 kD (c-Abl kinase) is purified by a two-step procedure overa Cobalt metal chelate column followed by an anion exchange column witha yield of 1-2 mg/L of Sf9 cells (Bhat et al., reference cited). Thepurity of the c-Abl kinase is >90% as judged by SDS-PAGE after Coomassieblue staining. The assay contains (total volume of 30 μL): c-Abl kinase(50 ng), 20 mM Tris-HCl, pH 7.5,10 mM MgCl₂, 10 μM Na₃VO₄, 1 mM DTT and0.06 μCi/assay [γ³³ P]-ATP (5 μM ATP) using 30 μg/mLpoly-Ala,Glu,Lys,Tyr-6:2:5:1 (Poly-AEKY, Sigma P1152) in the presence of1% DMSO. Reactions are terminated by adding 10 μL of 250 mM EDTA and 30μL of the reaction mixture is transferred onto Immobilon-PVDF membrane(Millipore, Bedford, Mass., USA) previously soaked for 5 min withmethanol, rinsed with water, then soaked for 5 min with 0.5% H₃PO₄ andmounted on vacuum manifold with disconnected vacuum source. Afterspotting all samples, vacuum is connected and each well rinsed with 200μL 0.5% H₃PO₄. Membranes are removed and washed on a shaker with 0.5%H₃PO₄ (4 times) and once with ethanol. Membranes are counted afterdrying at ambient temperature, mounting in Packard TopCount 96-wellframe, and addition of 10 μL/well of Microscint™ (Packard). Using thistest system, compounds of the formula I or I* show IC₅₀ values ofinhibition in the range of 0.001 to 100 μM, usually between 0.05 and 5μM.

The inhibition of VEGF-induced receptor autophosphorylation can beconfirmed with a further in vitro experiments in cells such astransfected CHO cells, which permanently express human VEGF-R2 receptor(KDR), are seeded in complete culture medium (with 10% fetal calfserum=FCS) in 6-well cell-culture plates and incubated at 37° C. under5% CO₂ until they show about 80% confluency. The compounds to be testedare then diluted in culture medium (without FCS, with 0.1% bovine serumalbumin) and added to the cells. (Controls comprise medium without testcompounds). After two hours of incubation at 37° C., recombinant VEGF isadded; the final VEGF concentration is 20 ng/ml. After a further fiveminutes incubation at 37° C., the cells are washed twice with ice-coldPBS (phosphate-buffered saline) and immediately lysed in 100 μl lysisbuffer per well. The lysates are then centrifuged to remove the cellnuclei, and the protein concentrations of the supernatants aredetermined using a commercial protein assay (BIORAD). The lysates canthen either be immediately used or, if necessary, stored at −20° C.

A sandwich ELISA is carried out to measure the VEGF-R2 phosphorylation:a monoclonal antibody to VEGF-R2 (for example Mab 1495.12.14; preparedby H. Towbin, Novartis or comparable monoclonal antibody) is immobilizedon black ELISA plates (OptiPlate™ HTRF-96 from Packard). The plates arethen washed and the remaining free protein-binding sites are saturatedwith 3% TopBlock® (Juro, Cat. # TB232010) in phosphate buffered salinewith Tween 20® (polyoxyethylen(20)sorbitane monolaurate, ICI/Uniquema)(PBST). The cell lysates (20 μg protein per well) are then incubated inthese plates overnight at 4° C. together with an antiphosphotyrosineantibody coupled with alkaline phosphatase (PY20:AP from Zymed). The(plates are washed again and the) binding of the antiphosphotyrosineantibody to the captured phosphorylated receptor is then demonstratedusing a luminescent AP substrate (CDP-Star, ready to use, with EmeraldII; Applied Biosystems). The luminescence is measured in a Packard TopCount Microplate Scintillation Counter. The difference between thesignal of the positive control (stimulated with VEGF) and that of thenegative control (not stimulated with VEGF) corresponds to VEGF-inducedVEGF-R2 phosphorylation (=100%). The activity of the tested substancesis calculated as percent inhibition of VEGF-induced VEGF-R2phosphorylation, wherein the concentration of substance that induceshalf the maximum inhibition is defined as the IC₅₀ (inhibitory dose for50% inhibition). Compounds of the formula I or I* here show an IC₅₀ inthe range of 0.0003 to 20 μM, preferably between 0.001 and 10 μM.

In analogy, VEGF-R1 inhibition can be shown as follows: The test isconducted using Fit-1 VEGF receptor tyrosine kinase. The detailedprocedure is as follows: 30 μl kinase solution (10 ng of the kinasedomain of Flt-1, Shibuya et al., Oncogene 5, 519-24 (1990)) in 20 mMTris-HCl pH 7.5, 3 mM manganese dichloride (MnCl₂), 3 mM magnesiumchloride (MgCl₂), 10 mM sodium vanadate, 0.25 mg/ml polyethylenglycol(PEG) 20 000, 1 mM dithiothreitol and 3 μg/ml poly(Glu, Tyr) 4:1 (Sigma,Buchs, Switzerland), 8 μM [³³P]-ATP (0.2 μCi), 1% dimethyl sulfoxide,and 0 to 100 μM of the compound of formula I or I* to be tested areincubated together for 10 min at room temperature. The reaction is thenterminated by the addition of 10 μl 0.25 M ethylenediamine tetraacetate(EDTA) pH 7. Using a multichannel dispenser (LAB SYSTEMS, USA), analiquot of 20 μl is applied to a PVDF (=polyvinyl difluoride) ImmobilonP membrane (Millipore, USA), through a Millipore microtiter filtermanifold and connected to a vacuum. Following complete elimination ofthe liquid, the membrane is washed 4 times successively in a bathcontaining 0.5% phosphoric acid (H₃PO₄) and once with ethanol, incubatedfor 10 min each while shaking, then mounted in a Hewlett PackardTopCount Manifold and the radioactivity measured after the addition of10 μl Microscint® (β-scinitillation counter liquid). IC₅₀ values aredetermined by linear regression analysis of the percentages ofinhibition of each compound in three conditions (as a rule 0.01, 0.1 and1 μmol). The IC₅₀ values that can be found with compounds of the formulaI or I* are in the range of 0.01 to 100 μM, preferably in the range from0.01 to 50 μM.

Flt3 kinase inhibition is determined as follows: The baculovirus donorvector pFbacG01 (GIBCO) is used to generate a recombinant baculovirusexpressing the amino acid region amino acids 563-993 of the cytoplasmickinase domain of human Flt-3. The coding sequence for the cytoplasmicdomain of Flt-3 is amplified by PCR from human c-DNA libraries(Clontech). The amplified DNA fragments and the pFbacG01 vector are madecompatible for ligation by digestion with BamH1 and HindIII. Ligation ofthese DNA fragments results in the baculovirus donor plasmid Flt-3(1.1).The production of the viruses, the expression of proteins in Sf9 cellsand the purification of the GST-fused proteins are performed as follows:Production of virus: Transfer vector (pFbacG01-Flt-3) containing theFlt-3 kinase domain is transfected into the DH10Bac cell line (GIBCO)and the transfected cells are plated on selective agar plates. Colonieswithout insertion of the fusion sequence into the viral genome (carriedby the bacteria) are blue. Single white colonies are picked and viralDNA (bacmid) is isolated from the bacteria by standard plasmidpurification procedures. Sf9 or Sf21 cells (American Type CultureCollection) are then transfected in flasks with the viral DNA usingCellfectin reagent.

Determination of small scale protein expression in Sf9 cells: Viruscontaining media is collected from the transfected cell culture and usedfor infection to increase its titre. Virus containing media obtainedafter two rounds of infection is used for large-scale proteinexpression. For large-scale protein expression 100 cm² round tissueculture plates are seeded with 5×10⁷ cells/plate and infected with 1 mLof virus-containing media (approx. 5 MOIs). After 3 days the cells arescraped off the plate and centrifuged at 500 rpm for 5 min. Cell pelletsfrom 10-20, 100 cm² plates, are resuspended in 50 mL of ice-cold lysisbuffer (25 mMTris-HCl, pH 7.5, 2 mM EDTA, 1% NP-40, 1 mM DTT, 1 mMPMSF). The cells are stirred on ice for 15 min and then centrifuged at5000 rpms for 20 min.

Purification of GST-tagged proteins: The centrifuged cell lysate isloaded onto a 2 mL glutathione-sepharose column (Pharmacia) and washedthree times with 10 mL of 25 mM Tris-HCl, pH 7.5, 2 mM EDTA, 1 mM DTT,200 mM NaCl. The GST-tagged protein is then eluted by 10 applications (1mL each) of 25 mM Tris-HCl, pH 7.5, 10 mM reduced-glutathione, 100 mMNaCl, 1 mM DTT, 10% Glycerol and stored at −70° C.

Measurement of enzyme activity: Tyrosine protein kinase assays withpurified GST-Flt-3 are carried out in a final volume of 30 μL containing200-1800 ng of enzyme protein (depending on the specific activity), 20mM Tris-HCl, pH 7.6, 3 mM MnCl₂, 3 mM MgCl₂, 1 mM DTT, 10 μM Na₃VO₄, 3μg/mL poly(Glu,Tyr) 4:1, 1% DMSO, 8.0 μM ATP and 0.1 μCi [γ³³ P] ATP).The activity is assayed in the presence or absence of inhibitors, bymeasuring the incorporation of ³³P from [γ³³P] ATP into thepoly(Glu,Tyr) substrate. The assay (30 μL) is carried out in 96-wellplates at ambient temperature for 20 min under conditions describedbelow and terminated by the addition of 20 μL of 125 mM EDTA.Subsequently, 40 μL of the reaction mixture is transferred ontoImmobilon-PVDF membrane (Millipore, Bedford, Mass., USA) previouslysoaked for 5 min with methanol, rinsed with water, then soaked for 5 minwith 0.5% H₃PO₄ and mounted on vacuum manifold with disconnected vacuumsource. After spotting all samples, vacuum is connected and each wellrinsed with 200 μL 0.5% H₃PO₄. Membranes are removed and washed 4× on ashaker with 1.0% H₃PO₄, once with ethanol. Membranes are counted afterdrying at ambient temperature, mounting in Packard TopCount 96-wellframe, and addition of 10 μL/well of Microscint™ (Packard). IC₅₀ valuesare calculated by linear regression analysis of the percentageinhibition of each compound in duplicate, at four concentrations(usually 0.01, 0.1,1 and 10 μM). One unit of protein kinase activity isdefined as 1 mmole of ³³P ATP transferred from [γ³³P] ATP to thesubstrate protein per minute per mg of protein at 37° C. The compoundsof the formula I or I* here show IC₅₀ values in the range between 0.005and 20 μM, preferably between 0.01 and 10 μM.

Bcr-Abl inhibition can be determined by a capture ELISA as follows: Themurine myeloid progenitor cell line 32Dcl3 transfected with the p210Bcr-Abl expression vector pGDp210Bcr/Abl (32D-bcr/abl) is obtained fromJ Griffin (Bazzoni et al., J. Clin Invest. 98, 521-8 (1996); Zhao etal., Blood 90, 4687-9 (1997)). The cells express the fusion bcr-ablprotein with a constitutively active abl kinase and proliferate growthfactor-independent. The cells are expanded in RPMI 1640 (AMIMED; cat#1-41F01), 10% fetal calf serum, 2 mM glutamine (Gibco) (“completemedium”), and a working stock is prepared by freezing aliquots of 2×10⁶cells per vial in freezing medium (95% fetal calf serum, 5%dimethylsulfoxide (SIGMA, D-2650). After thawing, the cells are usedduring maximally 10-12 passages for the experiments. The antibodyanti-abl SH3 domain cat. # 06-466 from Upstate Biotechnology is used forthe ELISA. For detection of bcr-abl phosphorylation, theanti-phosphotyrosine antibody Ab PY20, labelled with alkalinephosphatase (PY10(AP)) from ZYMED (cat. # 03-7722) is used. Ascomparison and reference compound,(N-(5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine,in the form of the methane sulfonate (monomesylate) salt (ST1571)(marketed as Gleevec® or Glivec®, Novartis), is used. A stock solutionof 10 mM is prepared in DMSO and stored at −20° C. For the cellularassays, the stock solution is diluted in complete medium in two steps(1:100 and 1:10) to yield a starting concentration of 10 μM followed bypreparation of serial three-fold dilutions in complete medium. Nosolubility problems are encountered using this procedure. The testcompounds of formula I or I* are treated analogously. For the assay,200'000 32D-bcr/abl cells in 50 μl are seeded per well in 96 well roundbottom tissue culture plates. 50 μl per well of serial threefolddilutions of the test compound are added to the cells in triplicates.The final concentration of the test compound range e.g. from 5 μM downto 0.01 μM. Untreated cells are used as control. The compound isincubated together with the cells for 90 min at 37° C., 5% CO₂, followedby centrifugation of the tissue culture plates at 1300 rpm (Beckman GPRcentrifuge) and removal of the supernatants by careful aspiration takingcare not to remove any of the pelleted cells. The cell pellets are lysedby addition of 150 μl lysis buffer (50 mM Tris/HCl, pH 7.4, 150 mMsodium chloride, 5 mM EDTA, 1 mM EGTA, 1% NP-40 (non-ionic detergent,Roche Diagnostics GmbH, Mannheim, Germany), 2 mM sodium ortho-vanadate,1 mM phenylmethyl sulfonylfluoride, 50 μg/ml aprotinin and 80 μg/mlleupeptin) and either used Immediately for the ELISA or stored frozen at−20° C. until usage.

The anti-abl SH3 domain antibody is coated at 200 ng in 50 μl PBS perwell to black ELISA plates (Packard HTRF-96 black plates; 6005207)overnight at 4° C. After washing 3× with 200 μl/well PBS containing0.05% Tween 20 (PBST) and 0.5% TopBlock (Juro, Cat. # TB 232010),residual protein binding sites are blocked with 200 μl/well PBST, 3%TopBlock for 4 h at room temperature, followed by incubation with 50 μllysates of untreated or test compound-treated cells (20 μg total proteinper well) for 3-4 h at 4° C. After 3 x washing, 50 μl/well PY20(AP)(Zymed) diluted to 0.5 μg/ml in blocking buffer is added and incubatedover-night (4 IC). For all incubation steps, the plates are covered withplate sealers (Costar, cat. # 3095). Finally, the plates are washedanother three times with washing buffer and once with deionized waterbefore addition of 90 μl/well of the AP substrate CPDStar RTU withEmerald II. The plates now sealed with Packard Top Seal™-A plate sealers(cat. # 6005185) are incubated for 45 min at room temperature in thedark and luminescence is quantified by measuring counts per second (CPS)with a Packard Top Count Microplate Scintillation Counter (Top Count).For the final optimized version of the ELISA, 50 μl of the lysates ofthe cells grown, treated and lysed in 96 well tissue culture plates, aretransferred directyl from these plates to the ELISA plates that areprecoated with 50 ng/well of the rabbit poylclonal ant-abl-SH3 domain AB06-466 from Upstate. The concentration of the anti-phosphotyrosine ABPY20 (AP) can be reduced to 0.2 μg/ml. Washing, blocking and incubationwith the luminescent substrate are as above. The quantification isachieved as follows: The difference between the ELISA readout (CPS)obtained for with the lysates of the untreated 32D-bcr/abl cells and thereadout for the assay background (all components, but without celllysate) is calculated and taken as 100% reflecting the constitutivelyphosphorylated bcr-abl protein present in these cells. The activity ofthe compound in the bcr-abl kinase activity is expressed as percentreduction of the bcr-abl phosphorylation. The values for the IC₅₀ aredetermined from the dose response curves by graphical inter- orextrapolation. The compounds of the formula I or I* here preferably showIC₅₀ values in the range from 20 nM to 200 μM.

In addition to or instead of inhibiting the above-mentioned proteinkinases, the compounds of formula I or I* also inhibit other tyrosineprotein kinases that are involved in the signal transmission mediated bytrophic factors, for example kinases of the src kinase family, such asespecially the c-Src kinase, members of the PDGF receptor tyrosineprotein kinase family, for example the PDGF receptor (PDGF-R), c-Kit,VEGF-R and/or FGF-R; all of which play a part in growth regulation andtransformation in animal, especially mammal cells, including humancells. An appropriate assay is described in Andrejauskas-Buchdunger etal., Cancer Res. 52, 5353-8 (1992).

The diaryl urea derivatives useful according to the invention,especially compounds of formula I or I*, that inhibit the protein kinaseactivities mentioned, especially tyrosine protein kinases mentionedabove and below, can therefore be used in the treatment of proteinkinase dependent diseases. Protein kinase dependent diseases areespecially proliferative diseases, preferably benign or especiallymalignant tumours (for example carcinoma of the kidneys, liver, adrenalglands, bladder, breast, stomach, ovaries, colon, rectum, prostate,pancreas, lungs, vagina or thyroid, sarcoma, glioblastomas and numeroustumours of the neck and head, as well as leukemias). They are able tobring about the regression of tumours and to prevent the formation oftumour metastases and the growth of (also micro) metastases. In additionthey can be used in epidermal hyperproliferation (e.g. psoriasis), inprostate hyperplasia, and in the treatment of neoplasias, especially ofepithelial character, for example mammary carcinoma. It is also possibleto use the compounds of formula I or I* in the treatment of diseases ofthe immune system insofar as several or, especially, individual tyrosineprotein kinases are involved; furthermore, the compounds of formula I orI* can be used also in the treatment of diseases of the central orperipheral nervous system where signal transmission by at least onetyrosine protein kinase, especially selected from those mentionedspecifically, is involved.

The p21ras oncogene is a major contributor to the development andprogression of human solid cancers and is mutated in 30% of all humancancers. The endogenous GTPase activity, if alleviated in ras mutatedcancer cells, mediates constitutive growth signals to down-streameffectors such as raf kinase. Inhibiting the raf kinase signallingpathway can therefore be used for inhibiting the effect of active ras.The diaryl urea derivatives useful according to the present invention,especially the compounds of formula I or I*, as ras inhibitors are thusespecially appropriate for the therapy of diseases related to rasoverexpression or overactivity.

Vascular endothelial growth factor receptor-2 (VEGF-R2; KDR) isselectively expressed on the primary vascular endothelium and isessential for normal vascular development. In order to grow beyondminimal size, tumors must generate new vascular supply. Anglogenesis, orthe sprouting of new blood vessels, is a central process in the growthof solid tumors. For many cancers, the extent of vascularization of atumor is a negative prognostic indicator signifying aggressive diseaseand increased potential for metastasis. Recent efforts to understand themolecular basis of tumor-associated angiogenesis have identified severalpotential therapeutic targets, including the receptor tyrosine kinasesfor the angiogenic factor vascular endothelial growth factor (VEGF) (seeZeng et al., J. Biol. Chem. 276(35), 32714-32719 (2001)). The diarylurea derivatives useful according to the present invention, especiallythe compounds of formula I or I*, as KDR inhibitors are thus especiallyappropriate for the therapy of diseases related to VEGF receptortyrosine kinase overexpression. Among these diseases, especiallyretinopathies, age-related macula degeneration, psoriasis,haemangioblastoma, haemangloma, arteriosclerosis, inflammatory diseases,such as rheumatoid or rheumatic inflammatory diseases, especiallyarthritis, such as rheumatoid arthritis, or other chronic inflammatorydisorders, such as chronic asthma, arterial or post-transplantationalatherosclerosis, endometriosis, and especially neoplastic diseases, forexample so-called solid tumors (especially cancers of thegastrointestinal tract, the pancreas, breast, stomach, cervix, bladder,kidney, prostate, ovaries, endometrium, lung, brain, melanoma, Kaposi'ssarcoma, squamous cell carcinoma of heand and neck, malignant pleuralmesotherioma, lymphoma or multiple myeloma) and liquid tumors (e.g.leukemias) are especially important.

Flt3 (FMD-like tyrosine kinase) is especially expressed in hematopoieticprogenitor cells and in progenitors of the lymphoid and myeloid series.Aberrant expression of the Flt3 gene has been documented in both adultand childhood leukemias including AML (acute myelogenous leukemia), AMLwith trilineage myelodysplasia (AML/TMDS), ALL (acute lymphoblasticleukemia), CML (chronic myelogenous leukemia) and myelodysplasticsyndrome (MDS), which are therefore the preferred diseases to be treatedwith compounds of the formula I or I*. Activating mutations in Flt3 havebeen found in approximately 25 to 30% of patients with AML. Thus thereis accumulating evidence for the role of Flt3 in human leukemias, andthe diaryl urea derivatives useful according to the invention,especially the compounds of the formula I or I*, as Flt3 inhibitors areespecially of use in the therapy of this type of diseases (see Tse etal., Leukemia 15(7), 1001-1010 (2001); Tomoki et al., Cancer Chemother.Pharmacol. 48 (Suppl. 1), S27-S30 (2001); Birkenkamp et al., Leukemia1(12), 1923-1921 (2001); Kelly et al., Neoplasia 9(1), 310-318 (2002)).

In chronic myelogeous leukemia (CML), a reciprocally balancedchromosomal translocation in hematopoietic stem cells (HSCs) producesthe BCR-ABL hybrid gene. The latter encodes the oncogenic Bcr-Abl fusionprotein. Whereas ABL encodes a tightly regulated protein tyrosinekinase, which plays a fundamental role in regulating cell proliferation,adherence and apoptosis, the BCR-ABL fusion gene encodes asconstitutively activated kinase, which transforms HSCs to produce aphenotype exhibiting deregulated clonal proliferation, reduced capacityto adhere to the bone marrow stroma and a reduces apoptotic response tomutagenic stimuli, which enable it to accumulate progressively moremalignant transformations. The resulting granulocytes fail to developinto mature lymphocytes and are released into the circulation, leadingto a deficiency in the mature cells and increased susceptibility toinfection. ATP-competitive inhibitors of Bcr-Abl have been describedwhich prevent the kinase from activating mitogenic and anti-apoptoticpathways (e.g. P-3 kinase and STAT5), leading to the death of theBCR-ABL phenotype cells and thereby providing an effective therapyagainst CML. The diaryl urea derivatives useful according to the presentinvention, especially the compounds of the formula I or I*, as Bcr-Ablinhibitors are thus especially appropriate for the therapy of diseasesrelated to its overexpression, especially leukemias, such as leukemias,e.g. CML or ALL.

Compounds of the formula I or I*, in view of their activity as PDGFreceptor inhibitors, are also especially appropriate in the treatment ofprolifeative diseases, especially small lung cancer, atherosclerosis,thrombosis, psoriasis, scleroderma or fibrosis.

There are also experiments to demonstrate the antitumor activity ofcompounds of the formula I or I* in vivo: The in vivo antitumor activityis tested, for example, using breast carcinoma cell lines, such as thethe human estrogen dependent breast carcinoma MCF-7 (ATCC: HTB22) orZR-75-1 (ATCC: CRL1500), or the estrogen-independen breast carcinomasMDA-MB468 (ATCC: HTB132) or MDA-MB231 (ATCC: HTB26); colon carcinomacell lines, such as the colon-carcinoma Colo 205 (ATCC: CCL222);glioblastoma cell lines, such as the glioblastomas U-87MG (ATCC: HTB14)or U-373MG (ATCC: HTB17); lung carcinoma cell lines, such as the “smallcell lung carcinomas” NCI—H69 (ATCC: HTB119) or NCI—H209 (ATCC: HTB172),or the lung carcinoma NCI—H596 (ATCC: HTB178); skin tumor cell lines,such as the melanomas Hs294T (ATCC: HTB140) or A375 (ATCC: CRL1619);tumor cell lines from the genitourinry systems, such as the ovarialcarcinoma NIH-Ovcar3 (ATCC: HTB161), as well as the prostate carcinomasDU145 (ATCC: HTB81) or PC-3 (ATCC: CRL1435), or the bladder carcinomaT24 (ATCC: HTB4); epithelial carcinomas, such as the epithelialcarcinoma KB31; or (especially with regard to leukemias) K562 cells(American Type Culture Collection, Mannassas, Va.) or human CFU-G cells(CFU-G stands for granulocyte colony forming unit, and it represents anearly but commited granulocyte forming precursor cell that circulates inthe blood stream or bone marrow) each of which is transplanted intofemale or male Balb/c nude mice. Other cell lines include leukemic celllines such as K-562, SUPB15, MEG01, Ku812F, MOLM-13, BaF3, CEM/0,JURKAT/0 or U87MG.

Tumors are obtained after subcutaneous injection of the respective cells(minimum 2×10⁶ cells in 100 ml phosphate buffered physiological saline)into the carrier mice (e.g. 48 mice per cell line). The resulting tumorsare passed serially through at least three subsequent transplantationsbefore treatment is started. Tumor fragments (about 25 mg each) areinjected s.c. into the left flank of the animals using a 13-gauge Trocarneedle under Forene narcosis (Abbott, Switzerland) for implantation.Mice transplanted with estrogen-dependent tumor are, in addition,supplied with an estrogen pellet (1.0 cm of a tube with a qualityappropriate for medical purposes, Dow Chemicals, with 5 mg estradiole,Sigma). The treatment is started routinely (that is at low orintermediate tumor burden), as soon as the tumor has reached an averagesize of 100 mm³. Tumor growth is determined once, twice or thrice weekly(depending on tumor growth of the cell line) and 24 h after the lasttreatment by measurement of the perpendicular diameter. In case oftumors, tumor volumes are determined according to the formula L×D×p/6(see Evans, B. D., Smith, I. E., Shorthouse, A. J. and Millar, J. J.,Brit. J. Cancer, 45: 466-468, 1982). The antitumor activity is expressedas T/C% (average increase of the tumor volume of treated animals dividedby the average increase of tumor volume in control animals multiplied by100). Tumor regression (%) represents the smallest mean tumor volumecompared to the mean tumor volume at the beginning of the treatment.Each animal in which the tumor reaches a diameter of more than 1,5 to 2cm³ is sacrificed. Leukemia burden is assessed by examining bothperipheral white blood count and weight of spleen and thymus in animalstumored with leukemia cell lines.

An exemplary (though not limiting) schedule for administration of adiaryl urea derivative, especially of formula I or I*, or a saltthereof, is daily administration, with preferably 1 to 3 daily dosagesfor a longer time, possibly until the disease is cured or, if onlypalliative treatment is achieved, for as long as required;alternatively, treatment e.g. for 5 days, and/or administration at days1, 4 and 9, with eventual repetition after a certain time withouttreatment is possible. Alternatively, treatment several times a day(e.g. 2 to 5 times) or treatment by continuous administration (e.g.infusion), e.g. at the time points indicated in the last sentence, arepossible. Generally, administration is orally or parenterally,preferably orally. The test compounds are preferably diluted in water orin sterile 0.9% saline.

All human tumor cell lines are obtained from the American Type CultureCollection (ATCC, Rockville, Md., USA) if not indicated otherwise andare cultivated in the suggested media with the corresponding additives(ATCC culture conditions), if not mentioned otherwise. The c-sis- andv-sis- transformed BALB/c 3T3 cells are obtained from Dr. C. Stiles(Dana Farber Cancer Institute, Boston, Mass., USA). They are cultured in“Dulbecco's modified Eagle's medium” (DMEM), that is supplemented with10% calf serum and Hygromycin B in a concentration of 0.2 mg/ml or G418in a concentration of 0.5 mg/mi. BALB/c AMuLV A.6R.1 cells (ATCC) arekept in DMEM, supplemented with 10% fetal calf serum.

The pharmacological activity of a diaryl urea derivative of the formulaI or I* may, for example, be demonstrated in a clinical study or in atest procedure as essentially described hereinafter.

Suitable clinical studies are, for example, open label non-randomized,dose escalation studies in patients with one of the tumor diseasesmentioned above. The beneficial effects on proliferative diseases can bedetermined directly through the results of these studies or by changesin the study design which are known as such to a person skilled in theart. The efficacy of the treatment can be determined in such studies,e.g., in case of tumors after 18 or 24 weeks by radiologic evaluation ofthe tumors every 6 weeks, in case of a leukaemia e.g. by determinationof the count of aberrant white blood cells, and by staining mononuclearcells and/or by means of determining minimum residual disease (MRD) e.g.by FACS-LPC MRD or PCR.

Alternatively, a placebo-controlled, double blind study can be used inorder to prove the benefits of the diaryl urea derivatives usefulaccording to the invention, especially the compounds of the formula I orI*, mentioned herein.

The diaryl urea derivatives useful according to the invention,especially the compounds of the formula I, preferably the novelcompounds of the formula I, can be prepared according to methods thatare known in the art, especially whereby

-   -   (a) for the synthesis of a compound of the formula I wherein X        NR if p is 0, or if p is 2 or 3, X is nitrogen which together        with (CH₂)_(p) and the bonds represented in dotted (interrupted)        lines (including the atoms to which they are bound) forms a        ring, and G. Z, A, A′, Y₁, Y₂, R, R₁, R₂, R₃, R₄, R₅, m, n, p        and r have the meanings given under formula I, an amino compound        of the formula II    -   wherein X is as just defined and R₄, R₅, A, A′, Y₁, Y₂, m, n, p,        r and the bonds represented in dotted (interrupted) lines have        the meanings given under formula I, is reacted with an        isocyanate of the formula III        O═C═N-G-Z   (III)    -   wherein G, Z, R₁, R₂ and R₃ are as defined for compounds of the        formula I, or    -   (b) for the synthesis of a compound of the formula I wherein m        is 0 (and thus Y₂ is missing), n is 1, Y₁ is O and G, Z, X, R₁,        R₂, R₃, R₄, R₅, A, A′, p and r are as defined for compounds of        the formula I, a hydroxy compound of the formula IV    -   wherein G, Z, X, R₁, R₂, R₃, R₅, p and the bonds represented in        dotted (interrupted) lines have the meanings given under formula        I, is etherified with a halo compound of the formula V    -   wherein R₄ and r have the meanings as defined for a compound of        formula I and Hal is halo, especially chloro, or    -   (c) for the synthesis of a compound of the formula I wherein p        is zero, X is CHK, especially CH₂, and G, Z, K, Y₁, Y₂, R₁, R₂,        R₃, R₄, R₅, A′, m, n and r have the meanings given for a        compound of the formula I, a carboxyl compound of the formula VI    -   wherein K is lower alkyl or preferably hydrogen and A, A′, Y₁,        Y₂, R₄, R₅, m, n and r have the meanings given for compounds of        the formula I, or a reactive derivative thereof, is condensed        with an amino compound of the formula VII        H₂N-G-Z   (VII)    -   wherein G, Z, R₁, R₂ and R₃ are as defined for compounds of the        formula I, or    -   (d) for the synthesis of a compound of the formula I wherein X        is NH, p is zero and G, Z, A, A′, Y₁, Y₂, R₁, R₂, R₃, R₄, R₅, m,        n and r have the meanings given under formula I, an isocyanate        of the formula VIII    -   wherein R₄, A, A′, Y₁, Y₂, m, n, r and R₅ are as defined for        compounds of the formula I, is reacted with an amino compound of        the formula IX        H₂N-G-Z   (IX)    -   wherein G, Z, R₁, R₂ and R₃ are as defined for compounds of the        formula I,

and, if desired, after reaction (a), (b), (c) or (d) an obtainablecompound of formula I is transformed into a different compound offormula I, a salt of an obtainable compound of formula I is transformedinto the free compound or a different salt, or an obtainable freecompound of formula I is transformed into a salt; and/or an obtainablemixture of isomers of compounds of formula I is separated into theindividual isomers;

where for all reactions mentioned functional groups in the startingmaterials that shall not take part in the reaction are, if required,present in protected form by readily removable protecting groups, andany protecting groups are subsequently removed.

The following reaction conditions are preferred, respectively:

Within the scope of this text, only a readily removable group that isnot a constituent of the particular desired end product of formula I isdesignated a “protecting group”, unless the context indicates otherwise.The protection of functional groups by such protecting groups, theprotecting groups themselves, and their cleavage reactions are describedfor example in standard reference works, such as J. F. W. McOmie,“Protective Groups in Organic Chemistry”, Plenum Press, London and NewYork 1973, in T. W. Greene and P. G. M. Wuts, “Protective Groups inOrganic Synthesis”, Third edition, Wiley, New York 1999, in “ThePeptides”; Volume 3 (editors: E. Gross and J. Meienhofer), AcademicPress, London and New York 1981, in “Methoden der organischen Chemie”(Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15/I,Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jeschkeit,“Aminosäuren, Peptide, Proteine” (Amino acids, Peptides, Proteins),Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and in JochenLehmann, “Chemie der Kohlenhydrate: Monosaccharide und Derivate”(Chemistry of Carbohydrates: Monosaccharides and Derivatives), GeorgThieme Verlag, Stuttgart 1974. A characteristic of protecting groups isthat they can be removed readily (i.e. without the occurrence ofundesired secondary reactions) for example by solvolysis, reduction,photolysis or alternatively under physiological conditions (e.g. byenzymatic cleavage).

A protecting group for an OH group, namely a tri-lower alkylsilyl group,such as tert-butyl-di-methylsilyl, can, for example, be removed in thepresence of fluoride anions, e.g. by reaction with an appropriateammonium fluoride, such as tert-butylammonium fluoride, or preferablywith HF in the presence of a nitrogen base, especially pyridine, in anaprotic solvent, especially an ether, such as tetrahydrofurane, anitrile, such as acetonitrile, or a mixture thereof, at temperaturesbetween 0 and 50° C., e.g. at room temperature.

Reactions (a) and (d) preferably take place in an appropriate solvent,e.g. an ether, such as tetrahydrofurane (other solvents, such astoluene, may also be present, especially in low amounts), preferably attemperatures in the range from 0 to 50° C., e.g. at room temperature.

Reaction (b), that is, the formation of ethers, preferably takes placein the presence of a metal alcoholate, especially an alkali metalalcoholate, such as potassium tert-butylate, in an appropriate solvent,such as N,N′-dimethypropyleneura or a di-lower alkyl-loweralkanoyl-amide, such as dimethylformamide, or mixtures thereof, atpreferred temperatures between 50° C. and the reflux temperature of thereaction mixture, for example at 100° C.

The ether formation can also take place under the conditions of theHartwig-Buchwald type etherification reactions (see e.g. Mann et al., J.Am. Chem. Soc. 121(13), 3224-5 (1999), or Aranyos et al., J. Am. Chem.Soc. 121, 4369-78 (1999)).

Reaction (c), that is, the formation of amide bonds, preferably takesplace under standard conditions for the formation of peptide bonds(condensation reaction). In a reactive derivative of a compound of theformula I, the carboxyl group is either functionalized as activatedester (reactive form). The reactive carboxyl groups are, however,preferably synthesized in situ (for example making use of reagentscustomary in peptide chemistry, e.g. for the preparation of1-hydroxybenzotriazole, succinimide- or N-hydroxysuccinimide esters, orin situ derivatisation with condensing agents, e.g. with carbodiimides,such as dicyclohexylcarbodiimide, with carbonylimidazole, withN-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate-N-oxide(HATU); with2-(1H-benzo-triazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborat(HBTU), with2-(pyridon-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TPTU); orbenzotriazol-1-yl-oxy-tris(dimethylamino)-phosphoniumhexafluorophosphate(BOP), or similar reagents). The condensation reaction preferably takesplace in the presence of a condensing agent, especially HBTU, in anaprotic polar solvent, preferably a N,N-di-(lower alkyl)-loweralkanoylamide, such as dimethylformamide, at preferred temperatures inthe range from 0 to 50° C., e.g. at room temperature.

Compounds of formula I can be transformed into different compounds offormula I.

Especially, the following transformations are of interest:

In compounds of the formula I wherein A and/or A′ is N, a N may beoxidised to an N→O by oxidation in the presence of a peroxide,especially a peroxybenzoic acid derivative, such as3-chloroperoxybenzoic acid, in the presence of a base, e.g. an alkalimetal carbonate, such as sodium carbonate, and in an appropriatesolvent, e.g. a halogenated hydrocarbon, such as chloroform or methylenechloride.

In compounds of the formula I where a lower alkoxy, especially methoxy,substituent R₄ is present, this substituent may be transformed into thecorresponding hydroxy substituent R₄, for example in an alcohol, such asethanol, in the presence of an acid, such as HCl, preferably at elevatedtemperatures, e.g. under reflux, or in the presence of a tri-loweralkylsilaneiodide, especially Me₃Si—I, in an appropriate solvent, e.g. achlorinated hydrocarbon, such as chloroform or methylene chloride, atelevated temperatures, for example at 40 to 60° C. The correspondinghydroxy group may then, by way of tautomerism transferring the hydrogento an adjacent carbon atom with a double bond, form an oxo group, thusleading, if only one of A and A′ is N, to a pyridin-on-yl moeity, ifboth are N, to a pyrimidin-on-yl moiety.

Salts of compounds of formula I having at least one salt-forming groupmay be prepared in a manner known per se. For example, salts ofcompounds of formula I having acid groups may be formed, for example, bytreating the compounds with metal compounds, such as alkali metal saltsof suitable organic carboxylic acids, e.g. the sodium salt of2-ethylhexanoic acid, with organic alkali metal or alkaline earth metalcompounds, such as the corresponding hydroxides, carbonates or hydrogencarbonates, such as sodium or potassium hydroxide, carbonate or hydrogencarbonate, with corresponding calcium compounds or with ammonia or asuitable organic amine, stoichiometric amounts or only a small excess ofthe salt-forming agent preferably being used. Acid addition salts ofcompounds of formula I are obtained in customary manner, e.g. bytreating the compounds with an acid or a suitable anion exchangereagent. Internal salts of compounds of formula I containing acid andbasic salt-forming groups, e.g. a free carboxy group and a free aminogroup, may be formed, e.g. by the neutralisation of salts, such as acidaddition salts, to the isoelectric point, e.g. with weak bases, or bytreatment with ion exchangers.

Salts can be converted in customary manner into the free compounds;metal and ammonium salts can be converted, for example, by treatmentwith suitable acids, and acid addition salts, for example, by treatmentwith a suitable basic agent.

Mixtures of isomers obtainable according to the invention can beseparated in a manner known per se into the individual isomers;diastereoisomers can be separated, for example, by partitioning betweenpolyphasic solvent mixtures, recrystallisation and/or chromatographicseparation, for example over silica gel or by e.g. medium pressureliquid chromatography over a reversed phase column, and racemates can beseparated, for example, by the formation of salts with optically puresalt-forming reagents and separation of the mixture of diastereoisomersso obtainable, for example by means of fractional crystallisation, or bychromatography over optically active column materials.

Intermediates and final products can be worked up and/or purifiedaccording to standard methods, e.g. using chromatographic methods,distribution methods, (re-)crystallization, and the like.

Starting Materials

Within the following description of the synthesis of starting materialsG, Z, X, Y₁, Y₂, R₁, R₂, R₃, R₄, R₅, A, A′, m, n, p and r have themeanings indicated for compounds of the formula I, if not indicatedotherwise. The starting materials of the formulae II-IX are known,commercially avaiable and/or can be prepared according to methods knownin the art; in particular, they can be prepared using processes asdescribed in the Examples.

In the subsequent description of some preferred synthesis methods forpreferred starting materials, functional groups that shall not take partin the respective reactions can be present in protected form and theprotective groups can be removed at appropriate stages; for protectinggroups, there introduction and removal, reference is made to thestandard text-books and methods already mentioned above.

A compound of the formula II, for example, wherein Y₁ is O and Y₂ isabsent or CH₂, n is 1 and m is 0 or 1, X is NH and p is zero ispreferably prepared by reacting a hydroxy compound of the formula X

wherein A, A′, R₄ and r have the meanings indicated for formula I,preferably only one of A and A′ is N, the other CH, and the OH is inpara-position to the N, is reacted with a compound of the formula XI

wherein R₅ is as defined for formula I, Z₁ is halo, especially bromo oriodo, and Y₂ is absent (m=0) or CH₂ (m=1), in the presence of a base,especially an alkali metal carbonate, such as potassium carbonate, andof CuBr or CuI, if required in a solvent, resulting in a compound of theformula XII,

wherein A, A′, R₄, R₅, Y₁, Y₂, n, m and r have the meaning given underformulae X and XI, which is then reduced with hydogen in the presence ofan appropriate catalyst, especially Raney-Co or more preferablyRaney-Ni, in an appropriate solvent, e.g. an alcohol, such as methanol,to yield the corresponding amino compound (X is NH, p is zero) of theformula II.

Alternatively, for the synthesis of a compound of the formula II whereinall moieties have the meanings given under formulae X, XI and XII,except that in addition X is NR wherein R has the meanings given forcompounds of the formula I, a compound of the formula XIII

wherein R₄ and r have the meanings indicated for formula I, Z₂ is halo,especially chloro, A is N or CH, A′ is N and Z₂ is preferably inp-position to N as A or A′, is reacted with a compound of the formulaXIV

wherein R has the meanings indicated for formula I, Y₂ and m as well asR₅ are as defined under formula XI (preferably, Y₂ is absent, m=0), inthe presence of an alkali metal alcoholate, such as potassiumtert-butylate, in an appropriate solvent, e.g. a N,N-di-loweralkyl-lower alkanoylamide, such as dimethylformamide, and/orN,N′-dimethylpropyleneurea, to yield the corresponding compound of theformula II. Still alternatively, a compound of the formula II whereineach of A and A′ is nitrogen, X is NH and the remaining moieties are asdefined for compounds of the formula II resulting from a compound of theformula XII, can be obtained by reacting a compound of the formula XIIIwherein A and A′ are N and R₄, r and Z₂ are as defined under formulaXIII, is reacted with a compound of the formula XV

wherein Y₂, m and R₅ have the meanings given for compounds of theformula XIV, in the presence of a base, especially an alkali metalhydroxide, such as sodium hydroxide, in an aqueous solvent, e.g. waterin mixture with a ketone, such as acetone, resulting in a compound ofthe formula XII wherein A is N, A′ is N, Y, is O, n is 1, Y₂ is CH₂(m=1) or absent (m=0), which is then reduced as described for a compoundof the formula XII to the corresponding amino compound of the formulaII.

Compounds of the formula II wherein X is nitrogen and p is 2 or 3, Y₁ is0 (n=1) and Y₂ is absent (m=0) or CH₂ (m=1), while A, A′, R₄, R₅ and rhave the meanings given under formula I, is preferably prepared byreacting a compound of the formula XVI

wherein D is CH₂ or CH═CH and Y₂, m and R₅ are as just defined, with acompound of the formula XIII as defined above in the presence of analkali metal alcoholate, such as potassium tert-butylate, in anappropriate solvent, e.g. a N,N-di-lower alkyl-lower alkanoylamide, suchas dimethylformamide, and/or N,N′-dimethylpropyleneurea, to yield thecorresponding compound of the formula XVII

wherein A, A′, R₄, R₅, r, Y₂, m and D are as just defined. The doublebond(s) in the ring with D are then reduced, preferably with anappropriate complex hydride, especially with sodium cyanoborhhydride(NaBH₃CN) in an organic acid, especially acetic acid, to thecorresponding compound of the formula II. Alternatively, first reductionof the double bond(s) in the ring with D and then the reaction with acompound of the formula XIII can lead to the compound of formula II.

A compound of the formula III or VIII can, for example, be synthesizedfrom the corresponding amine compound (with —NH₂ instead of the —N═C═O),e.g. by reaction with phosgene or triphosgene in an appropriate tertiarynitrogen base, such as pyridine.

Compounds of the formula IV are known in the art or can be preparedaccording to methods that are known in the art; for example, compoundsof the formula IV in which X is CHK, wherein K is lower alkyl orhydrogen, and p is zero can be obtained by condensation of a compound ofthe formula XVIII

wherein p and X are as just defined, or a reactive derivative thereof,with a compound of the formula VII as defined above; the reactivederivatives and the reaction conditions correspond to those mentionedabove for the reaction of a compound of the formula VI with a compoundof the formula VII. The result is the corresponding compound of theformula IV.

Compounds of the formula V, VI and VII are known, can be preparedaccording to methods that are known in the art or analogous to thosedescribed above and/or are commercially available.

Other starting materials are either known in the art, can be preparedaccording to methods that are known in the art, e.g. analogously to themethods described hereinabove or in the examples, and/or arecommercially available. Starting materials are also available accordingto or analogously to methods described in WO 00/42012, WO 00/41698, WO99/32436 and WO 99/32463.

The present invention relates also to novel starting materials and/orintermediates and to processes for their preparation. The startingmaterials used and the reaction conditions selected are preferably thosethat result in the compounds described as being preferred.

General Process Conditions

The following applies in general to all processes mentioned hereinbeforeand hereinafter, while reaction conditions specifically mentioned aboveor below are preferred:

All the above-mentioned process steps can be carried out under reactionconditions that are known per se, preferably those mentionedspecifically, in the absence or, customarily, in the presence ofsolvents or diluents, preferably solvents or diluents that are inerttowards the re-agents used and dissolve them, in the absence or presenceof catalysts, condensation or neutralising agents, for example ionexchangers, such as cation exchangers, e.g. in the H⁺ form, depending onthe nature of the reaction and/or of the reactants at reduced, normal orelevated temperature, for example in a temperature range of from about−100° C. to about 190° C., preferably from approximately −80° C. toapproximately 150° C., for example at from −80 to −60° C., at roomtemperature, at from −20 to 40° C. or at reflux temperature, underatmospheric pressure or in a closed vessel, where appropriate underpressure, and/or in an inert atmosphere, for example under an argon ornitrogen atmosphere.

At all stages of the reactions, mixtures of isomers that are formed canbe separated into the individual isomers, for example diastereoisomersor enantiomers, or into any desired mixtures of isomers, for exampleracemates or mixtures of diastereoisomers, for example analogously tothe methods described under “Additional process steps”.

The solvents from which those solvents that are suitable for anyparticular reaction may be selected include those mentioned specificallyor, for example, water, esters, such as lower alkyl-lower alkanoates,for example ethyl acetate, ethers, such as aliphatic ethers, for examplediethyl ether, or cyclic ethers, for example tetrahydrofurane ordioxane, liquid aromatic hydrocarbons, such as benzene or toluene,alcohols, such as methanol, ethanol or 1- or 2-propanol, nitriles, suchas acetonitrile, halogenated hydrocarbons, such as methylene chloride orchloroform, acid amides, such as dimethylformamide or dimethylacetamide, bases, such as heterocyclic nitrogen bases, for examplepyridine or N-methylpyrrolidin-2-one, carboxylic acid anhydrides, suchas lower alkanoic acid anhydrides, for example acetic anhydride, cyclic,linear or branched hydrocarbons, such as cyclohexane, hexane orisopentane, or mixtures of those solvents, for example aqueoussolutions, unless otherwise indicated in the description of theprocesses. Such solvent mixtures may also be used in working up, forexample by chromatography or partitioning.

The compounds, including their salts, may also be obtained in the formof hydrates, or their crystals may, for example, include the solventused for crystallization. Different crystalline forms may be present.

The invention relates also to those forms of the process in which acompound obtainable as intermediate at any stage of the process is usedas starting material and the remaining process steps are carried out, orin which a starting material is formed under the reaction conditions oris used in the form of a derivative, for example in protected form or inthe form of a salt, or a compound obtainable by the process according tothe invention is produced under the process conditions and processedfurther in situ. In the process of the present invention those startingmaterials are preferably used which result in new compounds of formula Idescribed at the beginning as being especially valuable. Specialpreference is given to reaction conditions that are identical oranalogous to those mentioned in the Examples.

Preferred Embodiments According to the Invention

In the following preferred embodiments, general expression can bereplaced by the corresponding more specific definitions provided aboveand below, thus yielding stronger preferred embodiments of theinvention.

Preferred is the USE of compounds of the formula I or I*, tautomersthereof or pharmaceutically acceptable salts thereof, where the tyrosineprotein kinase dependent disease to be treated is a proliferativedisease depending on any one or more of of the following tyrosineprotein kinases: ras, Abl, VEGF receptor tyrosine kinase, Flt3, and/orBcr-Abl activity.

Preferred is further the USE of a compound of the formula I or atautomer thereof, or pharmaceutically acceptable salts thereof, where,in the compound of the formula I G is either not present, loweralkylene, especially methylene or ethylene, or C₃-C₅cycloalkylene,especially cyclopropylene, and Z is a radical of the formula Ia, or G isnot present and Z is a radical of the formula Ib;

A is CH or N and A′ is N or N→O;

n is 1;

m is 0 or 1;

p is 0, 2 or 3;

r is 0 or 1;

X is NR if p is 0, wherein R is hydrogen or lower alkyl, or if p is 2 or3, X is nitrogen which together with (CH₂)_(p) and the bonds representedin dotted (interrupted) lines (including the atoms to which they arebound) forms a ring, or

X is CHK wherein K is hydrogen and p is zero,

with the proviso that the bonds represented in dotted lines, if p iszero, are absent;

Y, is O, S or CH₂;

Y₂ is O;

with the proviso that (Y₁)_(n)—(Y₂)_(m) does not include O—O, or S—Ogroups; each of R₁, R₂ and R₃, independently of the others, is hydrogen,lower alkyl, especially methyl, ethyl, n-propyl, isopropyl ortert-butyl, lower alkenyl, especially isopropenyl, hydroxy-lower alkyl,especially hydroxy-propyl, lower alkoxy, especially methoxy, halo,especially chloro or bromo, halo-lower alkyl, especiallytrifluoromethyl, halo-lower alkoxy, especially trifluoromethoxy ortrifluoroethoxy, amino-lower alkyl, especially aminomethyl, amino-loweralkoxy, especially aminoethoxy, di-lower alkyl-amino, especiallydiethylamino, hydroxy-lower alkyl-amino, especially hydroxy-propylamino,bis-(lower alkoxy-lower alkylyamino, especiallybis-(2-methoxy-ethyl)-amino, di-lower alkyl-amino-lower alkyl,especially dimethylaminomethyl, phenyl, morpholinyl, especiallymorpholin-4-yl, piperidyl, especially piperidin-1-yl, piperidyl-loweralkyl, especially piperidin-1-ylmethyl, lower alkyl-piperazinyl,especially 4-methyl-piperazin-1-yl or 4-ethyl-piperazin-1-yl, loweralkyl-piperazinyl-lower alkyl, especially 4-methyl-piperazin-1-ylmethylor 4-ethyl-piperazin-1-ylmethyl, pyridyl, especially pyridin-2-yl, orlower alkyl-imidazolyl, especially 2- or 4-methyl-imidazol-1-yl; if r is1, R₄ is lower alkyl, especially methyl, ethyl or ispropyl, hydroxy,aminocarbonyl, lower alkyl-carbonyl, especially methylcarbonyl,cyclohexyl, halo, especially chloro or fluoro, halo-lower alkyl,especially trifluoromethyl, lower alkoxy, especially methoxy, amino,lower alkyl-amino, especially methylamino, ethylamino, isopropylamino ortert-butylamino, di-lower alkyl-amino, especially dimethylamino, loweralkenyl-amino, especially prop-2-enylamino or but-3-enylamino, loweralkyl-carbonyl-amino, especially methylcarbonylamino, cyano, azido,hydroxy-phenyl-amino, especially 3- or 4-hydroxy-phenyl-amino, mono ortri-lower alkoxy-phenyl-amino, especially methoxy-phenyl-amino ortrimethoxy-phenyl-amino, lower alkoxy-halo-phenyl-amino, especiallymethoxy-fluoro-phenyl-amino, phenyl-lower alkylamino, especiallybenzylamino, (mono or di-lower alkoxy)-phenyl-lower alkylamino,especially methoxy-benzylamino or dimethoxy-benzylamino,aminosulfonyl-phenyl-lower alkylamino, especiallyaminosulfonyl-benzylamino, amino-lower alkoxy-phenyl-amino, especiallyaminoethoxy-phenyl-amino, lower alkyl-amino-sulfonyl-loweralkyl-phenylamino, especially methylamino-sulfonylmethyl-phenylamino,lower alkyl-piperazinyl-lower alkylamino, especially4-methylpiperazin-1-yl-propylamino, morpholinyl-lower alkylamino,especially morpholin-4-yl-propylamino, lower alkyl-piperidyl-amino,especially 1-methyl-piperidin-4-ylamino, tetrazolyl, especially1H-tetrazol-5-yl, lower alkyl-tetrazolyl, especially loweralkyl-tetrazol-5-yl such as 1-methyl-1H-tetrazol-5yl or2-methyl-2H-tetrazol-5-yl, or (di-lower alkyl)-amino-loweralkyl-tetrazolyl, especially (di-lower alkyl)-amino-loweralkyl-tetrazol-5-yl such as 2-(3-dimethylaminopropyl)-2H-tetrazol-5-yl;and

R₅ is most preferably hydrogen, or lower alkyl, especially methyl, orhalo, especially chloro. Especially preferred is the USE of a compoundof the formula I or a tautomer thereof, or pharmaceutically acceptablesalts thereof, where, in the compound of the formula I A and A′ are bothN,n is 1, m is 0, p is 0 or 2, r is 1, X is NH if p is 0, or if p is 2,X is nitrogen which together with (CH₂)₂ and the bonds represented indotted (interrupted) lines (including the atoms to which they are bound)forms a ring, Y₁ is O, G is not present, Z is a radical of the formulaIa, at least one of R₁, R₂ and R₃ is a basic organic moiety, R₄ is aminoor lower alkylamino and R₅ is hydrogen.

Preferred is further also the USE of a compound of the formula I* or atautomer thereof, or pharmaceutically acceptable salts thereof, where,in the compound of the formula I* A is CH, N or N→O and A′ is N or N→O,with the proviso that not more than one of A and A′ can be N→O;

n is 1;

m is 0;

p is 0, 2 or 3;

r is 0, 1 or 2;

X is NR if p is 0, wherein R is hydrogen or lower alkyl, or if p is 2 or3, X is nitrogen which together with (CH₂)_(p) and the bonds representedin dotted (interrupted) lines (including the atoms to which they arebound).forms a ring, or

X is CH₂ and p is zero,

with the proviso that the bonds represented in dotted lines, if p iszero, are absent;

Y₁ is 0 or CH₂;

each of R₁, R₂ and R₃ independently of the others, is hydrogen, loweralkyl, halo, especially bromo or chloro, halolower alkyl, especiallytrifluoromethyl, lower alkoxy, especially methoxy, halo-lower alkoxy,especially 2,2,2-trifluoroethoxy, phenyl, piperidyl, especiallypiperidin-1-yl, piperazinyl, especially piperazin-1-yl, morpholinyl,especially morpholine, thiomorpholinyl, especially thiomorpholino, orany two of them together form a lower alkylene-dioxy bridge bound viathe oxygen atoms, and the remaining one of these moieties is hydrogen orone of the moieties mentioned;

if r is not zero, R₄ is lower alkyl, especially methyl or ethyl, loweralkoxy, especially methoxy, lower alkanoylamino, especially acetylamino,hydroxyphenylamino, especially p-hydroxyphenylamino, amino-loweralkyl-oxyphenyl-amino, especially 4-[(2-aminoethyl)-oxyphenyl]-amino,sulfamoylphenylamino, especially 4-sulfamoylphenylamino,carbamo-ylphenylamino, especially 4-carbamoylphenylamino,[N-(hydroxy-lower alkyl)-carbamoyl]-phenylamino, especially[N-(2-hydroxyethyl)-carbamoyl]-phenylamino, halo, especially chloro, orhydroxyl; and

R₅ is hydrogen, lower alkyl or halo, especially hydrogen.

Preferred among the novel compounds of the formula I are those wherein Gis either not present, lower alkylene, especially methylene or ethylene,or C₃-C₅cycloalkylene, especially cyclopropylene, and Z is a radical ofthe formula Ia, or G is not present and Z is a radical of the formulaIb;

A is CH or N and A′ is N or N→O;

n is 1;

m is 0 or 1;

p is 0, 2 or 3;

r is 1;

X is NR if p is 0, wherein R is hydrogen or lower alkyl, or if p is 2 or3, X is nitrogen, which together with (CH₂)_(p) and the bondsrepresented in dotted (interrupted) lines (including the atoms to whichthey are bound) forms a ring, or

X is CHK wherein K is hydrogen and p is zero,

with the proviso that the bonds represented in dotted lines, if p iszero, are absent;

Y₁ is O, S or CH₂;

Y₂ is O;

with the proviso that (Y₁)_(n)—(Y₂)_(m) does not include O—O, or S—Ogroups;

each of R₁, R₂ and R₃, independently of the others, is hydrogen, loweralkyl, especially methyl, ethyl, n-propyl, isopropyl or tert-butyl,lower alkenyl, especially isopropenyl, hydroxy-lower alkyl, especiallyhydroxy-propyl, lower alkoxy, especially methoxy, halo, especiallychloro or bromo, halo-lower alkyl, especially trifluoromethyl,halo-lower alkoxy, especially trifluoromethoxy or trifluoroethoxy,amino-lower alkyl, especially aminomethyl, amino-lower alkoxy,especially aminoethoxy, di-lower alkyl-amino, especially diethylamino,hydroxy-lower alkyl-amino, especially hydroxy-propylamino, bis-(loweralkoxy-lower alkyl)-amino, especially bis-(2-methoxy-ethyl)-amino,di-lower alkyl-amino-lower alkyl, especially dimethylaminomethyl,phenyl, morpholinyl, especially morpholinyl, piperidyl, especiallypiperidin-1-yl, piperidyl-lower alkyl, especially piperidin-1-ylmethyl,lower alkyl-piperazinyl, especially 4-methyl-piperazin-1-yl or4-ethyl-piperazin-1-yl, lower alkyl-piperazinyl-lower alkyl, especially4-methyl-piperazin-1-ylmethyl or 4-ethyl-piperazin-1-ylmethyl, pyridyl,especially pyridin-2-yl, or lower alkyl-imidazolyl, especially 2- or4-methyl-imidazol-1-yl, with the proviso that if G is not present and Zis a radical of the formula Ia, R₁, R₂ and R₃ cannot all be hydrogen andwith the further proviso that if one of R₁, R₂ and R₃ is halo, the othertwo cannot both be hydrogen;

R₄ is lower alkyl, especially methyl, ethyl or ispropyl, hydroxy,aminocarbonyl, lower alkyl-carbonyl, especially methylcarbonyl,cyclohexyl, halo, especially chloro or fluoro, halo-lower alkyl,especially trifluoromethyl, lower alkoxy, especially methoxy, amino,lower alkyl-amino, especially methylamino, ethylamino, isopropylamino ortert-butylamino, di-lower alkyl-amino, especially dimethylamino, loweralkenyl-amino, especially prop-2-enylamino or but-3-enylamino, loweralkyl-carbonyl-amino, especially methylcarbonylamino, cyano, azido,hydroxy-phenyl-amino, especially 3- or 4-hydroxy-phenyl-amino, mono ortri-lower alkoxy-phenyl-amino, especially methoxy-phenyl-amino ortrimethoxy-phenyl-amino, lower alkoxy-halo-phenyl-amino, especiallymethoxy-fluoro-phenyl-amino, phenyl-lower alkylamino, especiallybenzylamino, (mono or di-lower alkoxy)-phenyl-lower alkylamino,especially methoxy-benzylamino or dimethoxy-benzylamino,aminosulfonyl-phenyl-lower alkylamino, especiallyaminosulfonyl-benzylamino, amino-lower alkoxy-phenyl-amino, especiallyaminoethoxy-phenyl-amino, lower alkyl-amino-sulfonyl-loweralkyl-phenylamino, especially methylamino-sulfonylmethyl-phenylamino,lower alkyl-piperazinyl-lower alkylamino, especially4-methylpiperazin-1-yl-propylamino, morpholinyl-lower alkylamino,especially morpholin-4-yl-propylamino, lower alkyl-piperidyl-amino,especially 1-methyl-piperidin-4-ylamino, tetrazolyl, especially1H-tetrazol-5-yl, lower alkyl-tetrazolyl, especially loweralkyl-tetrazol-5-yl such as 1-methyl-1H-tetrazol-5-yl or2-methyl-2H-tetrazol-5-yl, or (di-lower alkyl)-amino-loweralkyl-tetrazolyl, especially (di-lower alkyl)-amino-loweralkyl-tetrazol-5-yl such as 2-(3-dimethylaminopropyl)-2H-tetrazol-5-yl,with the proviso that if X is NH, R₄ is not aminocarbonyl or loweralkyl-carbonyl and with the further proviso that if n is 1, m is 0, p is0, r is 1, X is NH, Y₁ is O, G is not present and Z is a radical of theformula Ia, R₄, together with the benzene ring containing A and A′, doesnot form methylpyridinyl, 2-hydroxy-pyridinyl or1-H-2-oxo-1,2-dihydropyridin-4-yl;

R₅ is most preferably hydrogen, or lower alkyl, especially methyl, orhalo, especially chloro;

or a tautomer thereof;

or pharmaceutically acceptable salts thereof.

Very preferred among the novel compounds of the formula I are thosewherein A and A′ are both N, n is 1,m is 0, p is 0 or 2, r is 1, X is NHif p is 0, or if p is 2, X is nitrogen which together with (CH₂)₂ andthe bonds represented in dotted (interrupted) lines (including the atomsto which they are bound) forms a ring, Y, is O, G is not present, Z is aradical of the formula Ia, at least one of R₁, R₂ and R₃ is a basicorganic moiety, R₄ is amino or lower alkylamino and R₅ is hydrogen, or atautomer thereof, or pharmaceutically acceptable salts thereof.

Preferred among the novel compounds of the formula I* are those whereinA, A′, n, m, p, Y₁, Y₂, R₁, R₂, R₃ and R₄ have the meanings given underformula I* above, and r is 1 to 5, X is NR if p is 0, wherein R ishydrogen or an organic moiety, or if p is 2 or 3, X is nitrogen whichtogether with (CH₂)_(p) and the bonds represented in dotted(interrupted) lines (including the atoms to which they are bound) formsa ring, or

X is CH₂ and p is zero,

and, if p is zero, the bonds represented in dotted lines are absent;

with the proviso that if X is NH, each of R₄, independently of theothers, if present, is a moiety as defined under formula I* above butnot bound to the rest of formula I* via a —C(═O)—, —C(NR)— or —S(O₂)—bridge, and the substituents R₁, R₂ and R₃ are selected from thefollowing moieties, whereby positions (o=ortho, m=meta, p=para) areindicated with regard to the position where the ring is bound to therest of the molecule in formula I* (via the NH—C(═O)—X-moiety):

if only R₁ is other than hydrogen:

-   -   R₁=p-lower alkyl, especially p-methyl, p-ethyl, p-n-propyl;        m-halo-lower alkyl, especially m-trifluoromethyl; or phenyl,        p-piperidin-1-yl or p-piperazin-1-yl;

if both R₁ and R₂ are other than hydrogen:

-   -   R₁=m-halo-lower alkyl, especially m-trifluoromethyl, and        R₂=p-halo, especially p-bromo;    -   R₁=m-halo-lower alkyl, especially m-trifluoromethyl, and        R₂=p-halo-lower alkoxy, especially p-(2,2,2-trifluoroethoxy);    -   R₁=m-halo-lower alkyl, especially m-trifluoromethyl, and        R₂=m-lower alkoxy, especially m-methoxy;    -   R₁=m-halo-lower alkyl, especially m-trifluoromethyl, and        R₂=p-phenyl;    -   R₁=m-halo-lower alkyl, especially m-trifluoromethyl, and        R₂=p-piperidin-1-yl or p-piperazin-1-yl;    -   R₁=m-halo-lower alkyl, especially m-trifluoromethyl, and        R₂=p-N-morpholino or p-N-thiomorpholino;    -   R₁=m-lower alkoxy, especially m-methoxy, and R₂=p-halo,        especially p-bromo (less preferred);    -   R₁=m-lower alkoxy, especially m-methoxy, and R₂=p-halo-lower        alkoxy, especially p-2,2,2-trifluoroethoxy;    -   R₁=m-lower alkoxy, especially m-methoxy, and R₂=p-phenyl; or    -   R₁=m-lower alkoxy, especially m-methoxy, and R₂=p-piperidin-1-yl        or p-piperazin-1-yl;

or, if R₁, R₂ and R₃ are other than hydrogen:

-   -   R₁=m-lower alkoxy, especially m-methoxy; R₂=m-lower alkoxy,        especially m-methoxy; and R₃=p-lower alkoxy, especially        p-methoxy; or    -   R₁=lower alkoxy, especially methoxy, and R₂ and R₃ together form        a lower-alkylene-dioxy, especially —O—CH₂—CH₂—O—, bridge;

and R₅ is hydrogen, lower alkyl or halo, especially hydrogen; with theproviso that if n is 1, m is 0, p is 0, r is 1, X is NH and Y₁ is 0, R₄,together with the benzene ring containing A and A′, does not formmethylpyridinyl, 2-hydroxy-pyridin-4-yl or1-H-2-oxo-1,2-dihydropyridin-4-yl; or a tautomer thereof;

or pharmaceutically acceptable salts thereof.

Further preferred among the novel compounds of the formula I* are thosewherein A is CH, N or NO and A′ is N or NO, with the proviso that notmore than one of A and A′ can be N→O;

n is 1;

m is 0;

p is 0, 2 or 3;

r is 1 or 2;

X is NR if p is 0, wherein R is hydrogen or lower alkyl, or if p is 2 or3, X is nitrogen which together with (CH₂)_(p) and the bonds representedin dotted (interrupted) lines (including the atoms to which they arebound) forms a ring, or

X is CH₂ and p is zero,

with the proviso that the bonds represented in dotted lines, if p iszero, are absent;

Y₁ is 0 or CH₂;

R₁, R₂ and R₃ are selected from the following moieties, wherebypositions (o=ortho, m=meta, p=para) are indicated with regard to theposition where the ring is bound to the rest of the molecule in formulaI* (via the NH—C(═O)—X-moiety):

if only R₁ is other than hydrogen:

-   -   R₁=p-lower alkyl, especially p-methyl, p-ethyl, p-n-propyl;        m-halo-lower alkyl, especially m-trifluoromethyl; or phenyl,        p-piperidin-1-yl or p-piperazin-1-yl;

if both R₁ and R₂ are other than hydrogen:

-   -   R₁=m-halo-lower alkyl, especially m-trifluoromethyl, and        R₂=p-halo, especially p-bromo;    -   R₁=m-halo-lower alkyl, especially m-trifluoromethyl, and        R₂=p-halo-lower alkoxy, especially p-(2,2,2-trifluoroethoxy);    -   R₁=m-halo-lower alkyl, especially m-trifluoromethyl, and        R₂=m-lower alkoxy, especially m-methoxy;    -   R₁=m-halo-lower alkyl, especially m-trifluoromethyl, and        R₂=p-phenyl;    -   R₁=m-halo-lower alkyl, especially m-trifluoromethyl, and        R₂=p-piperidin-1-yl or p-piperazin-1-yl;    -   R₁=m-halo-lower alkyl, especially m-trifluoromethyl, and        R₂=p-N-morpholino or p-N-thiomorpholino;    -   R₁=m-lower alkoxy, especially m-methoxy, and R₂=p-halo,        especially p-bromo (less preferred);    -   R₁=m-lower alkoxy, especially m-methoxy, and R₂=p-halo-lower        alkoxy, especially p-2,2,2-trifluoroethoxy;    -   R₁=m-lower alkoxy, especially m-methoxy, and R₂=p-phenyl; or    -   R₁=m-lower alkoxy, especially m-methoxy, and R₂=p-piperidin-1-yl        or p-piperazin-1-yl;

or, if R₁, R₂ and R₃ are other than hydrogen:

-   -   R₁=m-lower alkoxy, especially m-methoxy; R₂=m-lower alkoxy,        especially m-methoxy; and R₃=p-lower alkoxy, especially        p-methoxy; or    -   R₁=lower alkoxy, especially methoxy, and R₂ and R₃ together form        a lower-alkylene-dioxy, especially —CH₂—CH₂—O—, bridge;

and, if r is not zero, R₄ is lower alkoxy, especially methoxy, loweralkanoylamino, especially acetylamino, hydroxyphenylamino, especiallyp-hydroxyphenylamino, amino-lower alkyl-oxyphenyl-amino, especially4-[(2-aminoethyl)-oxyphenyl]-amino, sulfamoylphenylamino, especially4-sulfamoylphenylamino, carbamoylphenylamino, especially4-carbamoylphenylamino, [N-(hydroxy-lower alkyl)-carbamoyl]-phenylamino,especially [N-(2-hydroxyethyl)-carbamoyl]-phenylamino, or halo,especially chloro;

and R₅ is halo, especially chloro, lower alkyl, especially methyl, orpreferably hydrogen:

or a tautomer thereof;

or pharmaceutically acceptable salts thereof.

Very preferred is a novel compound of the formula I or I*, as well astheir USE, provided in the Examples, or a pharmaceutically acceptablesalt thereof. Very preferred is also the method of synthesis for thesecompounds analogously to the methods described in the Examples.

Pharmaceutical Compositions

The invention relates also especially to pharmaceutical compositionscomprising a novel compound of the formula I or I*, to the use of acompound of the formula I or I* in the therapeutic (in a broader aspectof the invention also prophylactic) treatment or a method of treatmentof a (especially tyrosin) protein kinase dependent disease, especiallythe preferred diseases mentioned above, to the compounds of formula I orI* for said use and to the preparation of pharmaceutical preparations,especially for said uses.

The pharmacologically acceptable compounds of the present invention maybe used, for example, for the preparation of pharmaceutical compositionsthat comprise a pharmaceutically effective amount of a compound of theformula I or I*, or a pharmaceutically acceptable salt thereof, asactive ingredient together or in admixture with a significant amount ofone or more inorganic or organic, solid or liquid, pharmaceuticallyacceptable carriers.

The invention relates also to a pharmaceutical composition that issuitable for administration to a warm-blooded animal, especially a human(or to cells or cell lines derived from a warm-blooded animal,especially a human, e.g. lymphocytes), for the treatment or, in abroader aspect of the invention, prevention of (=prophylaxis against) adisease that responds to inhibition of tyrosin protein kinase activity,especially one of the diseases mentioned above as being preferred forUSE of a compound of formula I or I*, comprising an amount of a novelcompound of formula I or I*, or a pharmaceutically acceptable saltthereof, which is effective for said inhibition, together with at leastone pharmaceutically acceptable carrier.

The pharmaceutical compositions according to the invention are those forenteral, such as nasal, rectal or oral, or parenteral, such asintramuscular or intravenous, administration to warm-blooded animals(especially a human), that comprise an effective dose of thepharmacologically active ingredient, alone or together with asignificant amount of a pharmaceutically acceptable carrier. The dose ofthe active ingredient depends on the species of warm-blooded animal, thebody weight, the age and the individual condition, individualpharmacokinetic data, the disease to be treated and the mode ofadministration.

The invention relates also to a method of treatment for a disease thatresponds to inhibition of an (especially tyrosine) protein kinase,especially one of the diseases mentioned above as being preferred forUSE of a compound of formula I or I*; which comprises administering an(against the mentioned disease) prophylactically or especiallytherapeutically effective amount of a compound of formula I or I*according to the invention, especially to a warm-blooded animal, forexample a human, that, on account of one of the mentioned diseases,requires such treatment.

The dose of a compound of the formula I or I*, or a pharmaceuticallyacceeptable salt thereof to be administered to warm-blooded animals, forexample humans of approximately 70 kg body weight, is preferably fromapproximately 3 mg to approximately 30 g, more preferably fromapproximately 10 mg to approximately 1.5 g, most preferably from about100 mg to about 1000 mg per person per day, divided preferably into 1 to3 single doses which may, for example, be of the same size. Usually,children receive half of the adult dose.

The pharmaceutical compositions comprise from approximately 1% toapproximately 95%, preferably from approximately 20% to approximately90%, active ingredient. Pharmaceutical compositions according to theinvention may be, for example, in unit dose form, such as in the form ofampoules, vials, suppositories, drageesi tablets or capsules.

The pharmaceutical compositions of the present invention are prepared ina manner known per se, for example by means of conventional dissolving,lyophilising, mixing, granulating or confectioning processes.

Solutions of the active ingredient, and also suspensions, and especiallyisotonic aqueous solutions or suspensions, are one preferred form used,it being possible, for example in the case of lyophilised compositionsthat comprise the active ingredient alone or together with a carrier,for example mannitol, for such solutions or suspensions to be producedprior to use. The pharmaceutical compositions may be sterilised and/ormay comprise excipients, for example preservatives, stabilisers, wettingand/or emulsifying agents, solubilisers, salts for regulating theosmotic pressure and/or buffers, and are prepared in a manner known perse, for example by means of conventional dissolving or lyophilisingprocesses. The said solutions or suspensions may compriseviscosity-increasing substances, such as sodium carboxymethylcellulose,carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.

Suspensions in oil comprise as the oil component the vegetable,synthetic or semi-synthetic oils customary for injection purposes. Theremay be mentioned as such especially liquid fatty acid esters thatcontain as the acid component a long-chained fatty acid having from 8 to22, especially from 12 to 22, carbon atoms, for example lauric acid,tridecylic acid, myristic acid, pentadecylic acid, palmitic acid,margaric acid, stearic acid, arachidic acid, behenic acid orcorresponding unsaturated acids, for example oleic acid, elaidic acid,erucic acid, brasidic acid or linoleic acid, if desired with theaddition of antioxidants, for example vitamin E, β-carotene or3,5-di-tert-butyl-4-hydroxytoluene. The alcohol component of those fattyacid esters has a maximum of 6 carbon atoms and is a mono- orpoly-hydroxy, for example a mono-, di- or tri-hydroxy, alcohol, forexample methanol, ethanol, propanol, butanol or pentanol or the isomersthereof, but especially glycol and glycerol. The following examples offatty acid esters are therefore to be mentioned: ethyl oleate, isopropylmyristate, isopropyl palmitate, “Labrafil M 2375” (polyoxyethyleneglycerol trioleate, Gattefossé, Paris), “Miglyol 812” (tri-glyceride ofsaturated fatty acids with a chain length of C₈ to C₁₂, Hüls AG,Germany), but especially vegetable oils, such as cottonseed oil, almondoil, olive oil, castor oil, sesame oil, soybean oil and more especiallygroundnut oil.

Injection compositions are prepared in customary manner under sterileconditions; the same applies also to introducing the compositions intoampoules or vials and sealing the containers.

Pharmaceutical compositions for oral administration can be obtained bycombining the active ingredient with solid carriers, if desiredgranulating a resulting mixture, and processing the mixture, if desiredor necessary, after the addition of appropriate excipients, intotablets, dragèe cores or capsules. It is also possible for them to beincorporated into plastics carriers that allow the active ingredients todiffuse or be released in measured amounts.

Suitable carriers are especially fillers, such as sugars, for examplelactose, saccharose, mannitol or sorbitol, cellulose preparations and/orcalcium phosphates, for example tricalcium phosphate or calcium hydrogenphosphate, and binders, such as starch pastes using for example corn,wheat, rice or potato starch, gelatin, tragacanth, methylcellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone, and/or, if desired, disintegrators, such as theabove-mentioned starches, and/or carboxymethyl starch, crosslinkedpolyvinylpyrrolidone, agar, alginic acid or a salt thereof, such assodium alginate. Excipients are especially flow conditioners andlubricants, for example silicic acid, talc, stearic acid or saltsthereof, such as magnesium or calcium stearate, and/or polyethyleneglycol. Dragèe cores are provided with suitable, optionally enteric,coatings, there being used, inter alia, concentrated sugar solutionswhich may comprise gum arabic, talc, polyvinylpyrrolidone, polyethyleneglycol and/or titanium dioxide, or coating solutions in suitable organicsolvents, or, for the preparation of enteric coatings, solutions ofsuitable cellulose preparations, such as ethylcellulose phthalate orhydroxypropylmethylcellulose phthalate. Capsules are dry-filled capsulesmade of gelatin and soft sealed capsules made of gelatin and aplasticiser, such as glycerol or sorbitol. The dry-filled capsules maycomprise the active ingredient in the form of granules, for example withfillers, such as lactose, binders, such as starches, and/or glidants,such as talc or magnesium stearate, and if desired with stabilisers. Insoft capsules the active ingredient is preferably dissolved or suspendedin suitable oily excipients, such as fatty oils, paraffin oil or liquidpolyethylene glycols, it being possible also for stabilisers and/orantibacterial agents to be added. Dyes or pigments may be added to thetablets or dragèe coatings or the capsule casings, for example foridentification purposes or to indicate different doses of activeingredient.

A compound of the formula I or I* may also be used to advantage incombination with other antiproliferative agents. Such antiproliferativeagents include, but are not limited to aromatase inhibitors,antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors,microtubule active agents, alkylating agents, histone deacetylaseinhibitors, farnesyl transferase inhibitors, COX-2 inhibitors, MMPinhibitors, mTOR inhibitors, antineoplastic antimetabolites, platincompounds, compounds decreasing the protein kinase activity and furtherant-angiogenic compounds, gonadorelin agonists, anti-androgens,bengamides, bisphosphonates, antiproliferative antibodies andtemozolomide (TEMODAL®).

The term “aromatase inhibitors” as used herein relates to compoundswhich inhibit the estrogen production, i.e. the conversion of thesubstrates androstenedione and testosterone to estrone and estradiol,respectively. The term includes, but is not limited to steroids,especially exemestane and formestane and, in particular, non-steroids,especially aminoglutethimide, vorozole, fadrozole, anastrozole and, veryespecially, letrozole. Exemestane can be administered, e.g., in the formas it is marketed, e.g. under the trademark AROMASIN™. Formestane can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark LENTARON™. Fadrozole can be administered, e.g., in the form asit is marketed, e.g. under the trademark AFEMA™. Anastrozole can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark ARIMIDEX™. Letrozole can be administered, e.g., in the form asit is marketed, e.g. under the trademark FEMARA™ or FEMAR™.Aminoglutethimide can be administered, e.g., in the form as it ismarketed, e.g. under the trademark ORIMETEN™.

A combination of the invention comprising an antineoplastic agent whichis an aromatase inhibitor is particularly useful for the treatment ofhormone receptor positive breast tumors.

The term “antiestrogens” as used herein relates to compounds whichantagonize the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen can be administered, e.g., inthe form as it is marketed, e.g. under the trademark NOLVADEX™.Raloxifene hydrochloride can be administered, e.g., in the form as it ismarketed, e.g. under the trademark EVISTA™. Fulvestrant can beformulated as disclosed in U.S. Pat. No. 4,659,516 or it can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark FASLODEX™.

The term “topolsomerase I inhibitors” as used herein includes, but isnot limited to topotecan, irinotecan, 9-nitrocamptothecin and themacromolecular camptothecin conjugate PNU-166148 (compound A1 inWO99/17804). Irinotecan can be administered, e.g., in the form as it ismarketed, e.g. under the trademark CAMPTOSAR™. Topotecan can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark HYCAMTIN™.

The term “topoisomerase II inhibitors” as used herein includes, but isnot limited to the antracyclines doxorubicin (including liposomalformulation, e.g. CAELYX™), epirubicin, idarubicin and nemorubicin, theanthraquinones mitoxantrone and losoxantrone, and the podophillotoxinesetoposide and teniposide. Etoposide can be administered, e.g., in theform as it is marketed, e.g. under the trademark ETOPOPHOS™. Teniposidecan be administered, e.g., in the form as it is marketed, e.g. under thetrademark VM 26-BRISTOL™. Doxorubicin can be administered, e.g., in theform as it is marketed, e.g. under the trademark ADRIBLASTIN™.Epirubicin can be administered, e.g., in the form as it is marketed,e.g. under the trademark FARMORUBICIN™. Idarubicin can be administered,e.g., in the form as it is marketed, e.g. under the trademark ZAVEDOS™.Mitoxantrone can be administered, e.g., in the form as it is marketed,e.g. under the trademark NOVANTRON™.

The term “microtubule active agents” relates to microtubule stabilizingand microtubule destabilizing agents including, but not limited to thetaxanes paclitaxel and docetaxel, the vinca alkaloids, e.g.,vinblastine, especially vinblastine sulfate, vincristine especiallyvincristine sulfate, and vinorelbine, discodermolide and epothilones,such as epothilone B and D. Docetaxel can be administered, e.g., in theform as it is marketed, e.g. under the trademark TAXOTERE™. Vinblastinesulfate can be administered, e.g., in the form as it is marketed, e.g.under the trademark VINBLASTIN R.P.™. Vincristine sulfate can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark FARMISTIN™. Discodermolide can be obtained, e.g., as disclosedin U.S. Pat. No. 5,010,099.

The term “alkylating agents” as used herein includes, but is not limitedto cyclophosphamide, ifosfamide and melphalan. Cyclophosphamide can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark CYCLOSTIN™. Ifosfamide can be administered, e.g., in the formas it is marketed, e.g. under the trademark HOLOXAN™.

The term “histone deacetylase inhibitors” relates to compounds whichinhibit the histone deacetylase and which possess antiproliferativeactivity.

The term “farnesyl transferase inhibitors” relates to compounds whichinhibit the farnesyl transferase and which possess antiproliferativeactivity.

The term “COX-2 inhibitors” relates to compounds which inhibit thecyclooxygenase type 2 enyzme (COX-2) and which possess antiproliferativeactivity such as celecoxib (Celebrex®), rofecoxib (Vioxx®) andlumiracoxib (COX189).

The term “MMP inhibitors” relates to compounds which inhibit the matrixmetalloproteinase (MMP) and which possess antiproliferative activity.

The term “mTOR inhibitors” relates to compounds which inhibit themammalian target of rapamycin (mTOR) and which possess antiproliferativeactivity such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779and ABT578.

The term “antineoplastic antimetabolites” includes, but is not limitedto 5-fluorouracil, tegafur, capecitabine, cladribine, cytarabine,fludarabine phosphate, fluorouridine, gemcitabine, 6-mercaptopurine,hydroxyurea, methotrexate, edatrexate and salts of such compounds, andfurthermore ZD 1694 (RALTITREXED™), LY231514 (ALIMTA™), LY264618(LOMOTREXOL™) and OGT719.

The term “platin compounds” as used herein includes, but is not limitedto carboplatin, cisplatin and oxaliplatin. Carboplatin can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark CARBOPLAT™. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark ELOXATIN™.

The term “compounds decreasing the protein kinase activity and furtheranti-angiogenic compounds” as used herein includes, but is not limitedto compounds which decrease the activity of e.g. the VascularEndothelial Growth Factor (VEGF), the Epidermal Growth Factor (EGF),c-Src, protein kinase C, the Platelet-derived Growth Factor (PDGF),Bcr-Abl, c-Kit, Flt-3, the insulin-like Growth Factor I Receptor(IGF-IR) and the Cyclin-dependent kinases (CDKs), and anti-angiogeniccompounds having another mechanism of action than decreasing the proteinkinase activity.

Compounds which decrease the activity of VEGF are especially compoundswhich inhibit the VEGF receptor, especially the tyrosine kinase activityof the VEGF receptor, and compounds binding to VEGF, and are inparticular those compounds, proteins and monoclonal antibodiesgenerically and specifically disclosed in WO 98/35958 (describingcompounds of formula I), WO 00/09495, WO 00/27820, WO 00/59509, WO98/11223, WO 00/27819, WO 01/55114, WO 01/58899 and EP 0 769 947; thoseas described by M. Prewett et al in Cancer Research 59 (1999) 5209-5218,by F. Yuan et al in Proc. Natl. Acad. Sci. USA, vol. 93, pp.14765-14770,December 1996, by Z. Zhu et al in Cancer Res. 58, 1998, 3209-3214, andby J. Mordenti et al in Toxicologic Pathology, vol. 27, no. 1, pp 14-21,1999; in WO 00/37502 and WO 94/10202; Angiostatin™, described by M. S.O'Reilly et al, Cell 79, 1994, 315-328; and Endostatin™, described by M.S. O'Reilly et al, Cell 88,1997, 277-285; compounds which decrease theactivity of EGF are especially compounds which inhibit the EGF receptor,especially the tyrosine kinase activity of the EGF receptor, andcompounds binding to EGF, and are in particular those compoundsgenerically and specifically disclosed in WO 97/02266 (describingcompounds of formula IV), EP 0 564 409, WO 99/03854, EP 0520722, EP 0566 226, EP 0 787 722, EP 0 837 063, WO 98/10767, WO 97/30034, WO97/49688, WO 97/38983 and, especially, WO 96/33980;

compounds which decrease the activity of c-Src include, but are notlimited to, compounds inhibiting the c-Src protein tyrosine kinaseactivity as defined below and to SH2 interaction inhibitors such asthose disclosed in WO97/07131 and WO97/08193;

compounds inhibiting the c-Src protein tyrosine kinase activity include,but are not limited to, compounds belonging to the structure classes ofpyrrolopyrimidines, especially pyrrolo[2,3-d]pyrimidines, purines,pyrazopyrimidines, especially pyrazo[3,4-d]pyrimidines,pyrazopyrimidines, especially pyrazo[3,4-d]pyrimidines andpyridopyrimidines, especially pyrido[2,3-d]pyrimidines. Preferably, theterm relates to those compounds disclosed in WO 96/10028, WO 97/28161,W097/32879 and W097/49706;

compounds which decreases the activity of the protein kinase C areespecially those staurosporine derivatives disclosed in EP 0 296 110(pharmaceutical preparation described in WO 00/48571) which compoundsare protein kinase C inhibitors;

further specific compounds that decrease protein kinase activity andwhich may also be used in combination with the compounds of the presentinvention are Imatinib (Gleevec®/Glivec®), PKC412, Iressa™ (ZD1839),PK1166, PTK787, ZD6474, GW2016, CHIR-200131, CEP-7055/CEP-5214,CP-547632, KRN-633 and SU5416;

anti-angiogenic compounds having another mechanism of action thandecreasing the protein kinase activity include, but are not limited toe.g. thalidomide (THALOMID), celecoxib (Celebrex) and ZD6126.

The term “gonadorelin agonist” as used herein includes, but is notlimited to abarelix, goserelin and goserelin acetate. Goserelin isdisclosed in U.S. Pat. No. 4,100,274 and can be administered, e.g., inthe form as it is marketed, e.g. under the trademark ZOLADEX™. Abarelixcan be formulated, e.g. as disclosed in U.S. Pat. No. 5,843,901.

The term “anti-androgens” as used herein includes, but is not limited tobicalutamide (CASODEX™), which can be formulated, e.g. as disclosed inU.S. Pat. No. 4,636,505.

The term “bengamides” relates to bengamides and derivatives thereofhaving aniproliferative properties.

The term “bisphosphonates” as used herein includes, but is not limitedto etridonic acid, clodronic acid, tiludronic acid, pamidronic acid,alendronic acid, ibandronic acid, risedronic acid and zoledronic acid.“Etridonic acid” can be administered, e.g., in the form as it ismarketed, e.g. under the trademark DIDRONEL™. “Clodronic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark BONEFOS™. “Tiludronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark SKELID™. “Pamidronicacid” can be administered, e.g., in the form as it is marketed, e.g.under the trademark AREDIA™. “Alendronic acid” can be administered,e.g., in the form as it is marketed, e.g. under the trademark FOSAMAX™.“Ibandronic acid” can be administered, e.g., in the form as it ismarketed, e.g. under the trademark BONDRANAT™. “Risedronic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark ACTONEL™. “Zoledronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark ZOMETA™.

The term “antiproliferative antibodies” as used herein includes, but isnot limited to trastuzumab (Herceptin™), Trastuzumab-DM1, erlotinib(Tarceva™), bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553(anti-CD40) and 2C4 Antibody.

For the treatment of acute myeloid leukemia (AML), compounds of formulaI or I* can be used in combination with standard leukemia therapies,especially in combination with therapies used for the treatment of AML.In particular, compounds of formula I or I* can be administered incombination with e.g. famesyltransferase inhibitors and/or other drugsuseful for the treatment of AML, such as Daunorubicin, Adriamycin,Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum andPKC412.

The structure of the active agents identified by code nos., generic ortrade names may be taken from the actual edition of the standardcompendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

The above-mentioned compounds, which can be used in combination with acompound of the formula I or I*, can be prepared and administered asdescribed in the art such as in the documents cited above.

EXAMPLES

The following Examples serve to illustrate the invention withoutlimiting the scope thereof.

Abbreviations:

abs. absolute

AcOEt ethyl acetate

AcOH acetic acid

Anal. elemental analysis (for indicated atoms, difference betweencalculated and measured value ≦0.4%)

brine saturated solution of NaCl in water

cat. catalyst

conc. concentrated

d day(s)

decomp. decomposition

DIBAH diisobutyl-aluminium-hydride

DIEA diisopropyl-ethyl-amine

DMF dimethyl formamide

DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)pyrlmidinone

DMEU 1,3-dimethyl-2-imidazolidinone

DMSO dimethylsulfoxide

DMSO-d₈ per-deuterated dimethylsulfoxide

ether diethylether

EtOH ethanol

equiv equivalent(s)

Ex. Example

h hour(s)

HPLC high pressure liquid chromatography

L litre(s)

Me methyl

min minute(s)

m.p. melting point

MPLC medium pressure liquid chromatography (Combi Flash system)

NEt₃ triethylamine

NMM N-methylmorpholine

NMR Nuclear Magnetic Resonance

R_(f) ratio of fronts (thin layer chromatography)

rt room temperature

TBS tert-butyl-dimethylsilyl

TBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate

THF tetrahydrofuran (distilled from Na/benzophenone)

TFA trifluoroacetic acid

TLC thin layer chromatography

TPTU O-(2-oxo-1(2H)-pyridyl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate

t_(R) retention time (HPLC)

triphosgene bis(trichloromethyl)carbonate

Tween 80 polyoxyethylen(20)sorbitane monooleate (trademark of ICI,Uniquema)

HPLC Conditions

System 1: HPLC is performed on an Agilent HP 1100 using a Nucleosil100-3 C18 HD 125×4.0 mm column (1 ml/min; Linear gradient 20-100% CH₃CN(0.1% TFA) and H₂O (0.1% TFA) in 7 min).

System 2: Linear gradient 2-100% CH₃CN (0.1% TFA) and H₂O (0.1% TFA) in10 min +2 min 100% CH₃CN (0.1% TFA); detection at 215 nm, flow rate 0.7ml/min at 25 or 30° C. Column: Nucleosil 120-3 C18 (125×3.0 mm).

System 3: Linear gradient 20-100% CH₃CN (0.1% TFA) and H₂O (0.1% TFA) in13 min +5 min 100% CH₃CN (0.1% TFA); detection at 215 nm, flow rate 1m/min at 25 or 30° C. Column: Nucleosil 120-3 C18 (125×3.0 mm).

Example 1 N-(4-pyridin-4-yl-oxy-phenyl)-N′-(4-ethyl-phenyl)-urea

A solution of pyridine (3.46 ml, 43 mmol), 4-ethyl aniline (0.69 ml,5.37 mmol) and phosgene (11.1 ml, 20% in toluene; 21.5 mmol) in CH₂Cl₂(66 mL) is stirred at 0° C. overnight. After concentrating under reducedpressure, the reaction mixture is taken in THF (26 ml), filtrated, andadded to a solution of 4-(pyridin-4-yl-oxy)-phenylamine (Stage 1.1; 0.5g, 2.69 mmol) and pyridine (0.43 ml, 0.43 mmol) in THF (3.3 ml) andstirred at rt for 24 h. The reaction solution is filtered over silicagel (30 g), taken up in AcOEt (100 ml), washed with H₂O (20 ml), NaHCO₃(5%, 20 ml), and brine (20 ml, 2×), dried over Na₂SO₄, concentratedunder reduced pressure, and flash chromatographed (silica gel, 2×18 cm;AcOEt/hexane=2:1→4:1) giving compound of Example 1 as a colorless solid;M+H=334, ¹H-NMR (400 MHz, DMSO-d₆): 8.70 (s, 1H, NH), 8.60 (s, 1H, NH),8.44 (d, Hz, 6.5 Hz, 2H, pyridinyl), 7.54 (d, 9.5 Hz, 2H,4-ethyl-phenyl), 7.37 (d, 9.5 Hz, 2H, oxo-phenyl-amine), 7.11 (d/d, 9.5Hz, 4H, oxo-phenyl-amine/4-ethyl-phenyl), 6.89 (d, 6.5 Hz, 2H,pyridinyl), 2.55 (qu, 7.5 Hz, 2H, CH₂), 1.16 (t, 7.5 hz, 3H, CH₃); R_(f)(AcOEt/hexane=2:1): 0.16; m.p.=166.5-168° C.

The starting material is prepared as follows:

Stage 1.1: (4-(pyridin-4-yl-oxy)-phenyl-amine)

A solution of 4-aminophenol (15 g, 0.135 mol), 4-chloropyridinehydrochloride (22.5 g, 0.148 mol), and KOtBu (45.8 g, 0.404 mol) in DMPU(208 ml) and DMF (52 ml) is stirred at 100° C. for 24 h, cooled to rt,poured into H₂O (0.6 L), and extracted with AcOEt (150 ml, 6×). Thecombined organic phases are washed with H₂O (100 ml, 2×), brine (100 ml,2×), dried (Na₂SO₄), concentrated under reduced pressure, and flashchromatographed (silica gel, 4.5×25 cm; AcOEt/hexane=1:9→3:7) to givethe title compound of Stage 1.1 as a colorless solid: M+H=187.2; ¹H-NMR(400 MHz, DMSO-d₆): 8.37 (d, 6.5 Hz, 2H, pyridinyl), 6.79 (d, 9.5 Hz,2H, phenyl), 6.78 (d, 9.5 Hz, 2H, pyridinyl) 5.12 (s, 2H, NH₂); R_(f)(AcOEt/CH₂Cl₂=3:7): 0.23; m.p.=165.8-166.6° C.

Compounds of Examples 2-15 are synthesized analogously to thepreparation of the compound of Example 1 via urea formation of thecorresponding aryl isocyanates and 4-(pyridin-4-yl-oxy)phenylamine,methyl-[4-(pyridin-4-yl-oxy)-phenyl]amine,4-(pyridin-4-ylmethyl)-phenylamine ormethyl-[4-(pyridin-4-ylmethyl)-phenyl]amine, respectively. Structuresand analytical data are given below (Table 1).

Starting materials: Methyl-[4-(pyridin-4-yl-oxy)-phenyl]amine for thesynthesis of compounds of Examples 5-8 is prepared according to theprocedure of the preparation of the compound of Stage 1.1. After flashchromatography, the product is further purified by Kugelrohrdistillation (110° C., 0.3 mbar) and crystallized from AcOEt/hexane:M+H=201.1; ¹H-NMR (400 MHz, DMSO-d₆): 8.37 (d, 6.5 Hz, 2H, pyridinyl),6.78 (d, 9.5 Hz, 2H, pyridinyl), 6.56 (d, 9.5 Hz, 2H, phenyl), 5.71(s/broad, 1H, NH), 2.65 (d, 2.5 Hz, 3H, CH₃—N); R_(f)(acetone/CH₂Cl₂=3:7): 0.23. TABLE 1 Structures and analytical data ofcompounds of Examples 2-15

Ex. Y₁ X R₁, R₂ Analytical data 2 O NH 3-CF₃, - M − H = 372.1; ¹H-NMR(400 MHz, DMSO-d₆): 9.07 (s, 1H, NH), 8.95 (s, 1H, NH), 8.44 (d, Hz, 6.5Hz, 2H, pyridinyl), 8.02 (s, 1H, 3-CF₃-phenyl), 7.58 (d, 9.5 Hz, 2H,oxo-phenyl-amine), 7.5 (d, 8 Hz, 1H, 3- CF₃-phenyl), 7.53 (t, 8.0 Hz,1H, 3-CF₃-phenyl), 7.30 (d, 8.0 Hz, 1H, 3-CF₃-phenyl), 7.14 (d, 9.5 Hz,2H, oxo-phenyl-amine), 6.89 (d, 6.5 Hz, 2H, pyridinyl); R_(f)(AcOEt/hexane = 2:1): 0.12; m.p. = 147-149° C.. 3 O NH 4-n-Propyl, - M +H = 348.3; ¹H-NMR (400 MHz, DMSO-d₆): 8.73 (s, 1H, NH), 8.56 (s, 1H,NH), 8.42 (d, Hz, 6.5 Hz, 2H, pyridinyl), 7.55 (d, 9.5 Hz, 2H, 4-propyl-phenyl), 7.37 (d, 9.5 Hz, 2H, oxo-phenyl-amine), 7.09 (d/d, 9.5 Hz, 4H,oxo-phenyl-amine/4-propyl- phenyl), 6.84 (d, 6.5 Hz, 2H, pyridinyl),2.47 (t, 7.5 Hz, 2H, CH₂), 1.56 (sext, 7.5 Hz, 2H, CH₂, 0.88 (t, 7.5 hz,3H, CH₃); R_(f) (AcOEt/hexane = 2:1): 0.18; m.p. = 173-174.5° C. 4 O NH4-Methyl, - M + H = 320.1; ¹H-NMR (400 MHz, DMSO-d₆): 8.73 (s, 1H, NH),8.54 (s, 1H, NH), 8.40 (d, Hz, 6.5 Hz, 2H, pyridinyl), 7.54 (d, 9.5 Hz,2H, 4-methyl- phenyl), 7.32 (d, 9.5 Hz, 2H, oxo-phenyl-amine), 7.09(d/d, 9.5 Hz, 4H, oxo-phenyl-aminel 4-methyl- phenyl), 6.85 (d, 6.5 Hz,2H, pyridinyl), 2.49 (s, 3H, CH₃); R_(f) (AcOEt/hexane = 2:1): 0.15;m.p. = 190.5- 192° C.. 5 O NMe 4-Ethyl, - M + H = 348.1; ¹H-NMR (400MHz, DMSO-d₆): 8.49 (d, Hz, 6.5 Hz, 2H, pyridinyl), 8.10 (s, 1H, NH),7.39 (d, 9.5 Hz, 2H, 4-ethyl-phenyl), 7.22 (d, 9.5 Hz, 2H,oxo-pheny/-amine), 7.07 (d, 9.5 Hz, 4H, oxo-phenyl-amine), 7.07 (d, 9.5Hz, 2H, 4-ethyl- phenyl), 7.00 (d, 6.5 Hz, 2H, pyridinyl), 3.26 (s, 3H,CH₃—N), 2.49 (qu, 7.5 Hz, 3H, CH₂), 1.11 (t, 7.5 Hz, 3H, CH₃); R_(f)(AcOEt/hexane = 2:1): 0.10; oil. 6 O NMe 3-CF₃, - M + H = 388.2; ¹H-NMR(400 MHz, DMSO-d₆): 8.53 (s, 1H, NH), 8.48 (d, Hz, 6.5 Hz, 2H,pyridinyl), 7.83 (s, 1H, 3-CF₃-phenyl), 7.74 (d/broad, 8.0 Hz, 1H,—CF₃-phenyl), 7.44 (t, 8.0 Hz, 1H, 3-CF₃-phenyl), 7.41 (d, 9.5 Hz, 2H,oxo-phenyl-amine), 7.28 (d/broad, 8.0 Hz, 1H, —CF₃-phenyl), 7.19 (d, 9.5Hz, 2H, oxo-phenyl-amine), 6.97 (d, 6.5 Hz, 2H, pyridinyl); R_(f)(AcOEt/hexane = 2:1): 0.26; m.p. = 126-128.5° C.. 7 O NMe 4-n-Propyl, -M + H = 362.1; ¹H-NMR (400 MHz, DMSO-d₆): 8.46 (d, Hz, 6.5 Hz, 2H,pyridinyl), 8.09 (s, 1H, NH), 7.41 (d, 9.5 Hz, 2H, 4-propyl-phenyl),7.35 (d, 9.5 Hz, 2H, oxo-phenyl-amine), 7.19 (d, 9.5 Hz, 4H,oxo-phenyl-amine), 7.02 (d, 9.5 Hz, 2H, 4-propyl- phenyl), 6.97 (d, 6.5Hz, 2H, pyridinyl), 3.13 (s, 3H, CH₃—N), 2.49 (t, 7.5 Hz, 3H, CH₂), 1.53(sext, 7.5 Hz, 2H, CH₂), 0.84 (t, 7.5 Hz, 3H, CH₃); R_(f) (AcOEt/hexane= 2:1): 0.38; oil. 8 O NMe 4-Methyl, - M + H = 334.2; ¹H-NMR (400 MHz,DMSO-d₆): 8.48 (d, Hz, 6.5 Hz, 2H, pyridinyl), 8.07 (s, 1H, NH), 7.41(d, 9.5 Hz, 2H, 4-methyl-phenyl), 7.31 (d, 9.5 Hz, 2H,oxo-phenyl-amine), 7.19 (d, 9.5 Hz, 4H, oxo-phenyl-amine), 7.03 (d, 9.5Hz, 2H, 4-methyl- phenyl), 6.98 (d, 6.5 Hz, 2H, pyridinyl), 3.24 (s, 3H,CH₃—N), 2.20 (s, 3H, CH₃); R_(f) (AcOEt/hexane = 2:1): 0.17; oil. 9 O NH3-CF₃, M + H = 452.1/454.1; ¹H-NMR (400 MHz, DMSO-d₆): 4-Br 9.18 (s, 1H,NH), 8.96 (s, 1H, NH), 8.42 (d, Hz, 6.5 Hz, 2H, pyridinyl), 8.11 (s, 1H,Br/CF₃-phenyl), 7.75 (d, 8.0 Hz, 1H, Br/CF₃-phenyl), 7.56 (d, 8.0 Hz,1H, Br/CF₃-phenyl), 7.54 (d, 9.5 Hz, 2H, oxo-phenyl- amine), 7.11 (d,9.5 Hz, 2H, oxo-phenyl-amine), 6.84 (d, 6.5 Hz, 2H, pyridinyl); R_(f)(Ace- tonitrile/CH₂Cl₂ = 1:3): 0.22; m.p. = 180-183° C.. 10 O NH 3-CF₃,M + H = 472.1; ¹H-NMR (400 MHz, DMSO-d₆): 8.89 4-O—CH₂—CF₃ (s, 1H, NH),8.85 (s, 1H, NH), 8.42 (d, Hz, 6.5 Hz, 2H, pyridinyl), 7.88 (d, 3.0 Hz,1H, O—CH₂—CF₃/CF₃- phenyl), 7.75 (dd, 8.0 Hz, 3.0 Hz, 1H, O—CH₂—CF₃/CF₃-phenyl), 7.54 (d, 9.5 Hz, 2H, oxo-phenyl- amine), 7.31 (d, 8.0 Hz,1H, O—CH₂—CF₃/CF₃-phenyl), 7.08 (d, 9.5 Hz, 2H, oxo-phenyl-amine), 6.89(d, 6.5 Hz, 2H, pyridinyl), 4.90 (qu, 7.5 Hz, 2H, CH₂); R_(f)(MeOH/CH₂Cl₂ = 5:95): 0.15; m.p. = 188.5-190.5° C.. 11 O NH 5-CF₃, M + H= 404.1; ¹H-NMR (400 MHz, DMSO-d₆): 9.07 3-OMe (s, 1H, NH), 8.87 (s, 1H,NH), 8.40 (d, Hz, 6.5 Hz, 2H, pyridinyl), 7.55 (d, 9.5 Hz, 2H,oxo-phenyl- amine), 7.48 (s, 1H, CH₃—O—/CF₃-phenyl), 7.24 (s, 1H,O—CH₃/CF₃-phenyl ), 7.09 (d, 9.5 Hz, 2H, oxo- phenyl-amine), 6.84 (d,6.5 Hz, 2H, pyridinyl), 6.80 (s, 1H, CH₃—O—/CF₃-phenyl), 3.79 (s, 3H,CH₃—O); R_(f) (MeOH/CH₂Cl₂ = 1:3): 0.19; m.p. = 162.5-164.5° C.. 12 CH₂NH 4-n-Propyl, - M + H = 346.3; ¹H-NMR (400 MHz, DMSO-d₆): 8.58 (s, 1H,NH), 8.50 (s, 1H, NH), 8.44 (d, Hz, 6.5 Hz, 2H, pyridinyl), 7.36 (d, 9.5Hz, 2H, 4-propyl- phenyl), 7.33 (d, 9.5 Hz, 2H, oxo-phenyl-amine), 7.22(d, 6.5 Hz, 2H, pyridinyl), 7.13/7.04 (d/d, 9.5 Hz, 4H,oxo-phenyl-amine/4-propyl-pheny/), 3.87 (s, 2H, aryl-CH₂-aryl), 2.48 (t,7.5 Hz, 2H, CH₂), 1.56 (sext, 7.5 Hz, 2H, CH₂, 0.86 (t, 7.5 hz, 3H,CH₃); R_(f) (acetone/CH₂Cl₂ = 1:3): 0.27; m.p. = 164- 166° C.. 13 CH₂ NH4-Ethyl, - M + H = 332.1; ¹H-NMR (400 MHz, DMSO-d₆): 8.54 (s, 1H, NH),8.50 (s, 1H, NH), 8.43 (d, Hz, 6.5 Hz, 2H, pyridinyl), 7.38/7.33 (d/d,9.5 Hz, 4H, 4-ethyl- phenyl/, oxo-phenyl-amine), 7.19 (d, 6.5 Hz, 2H,pyridinyl), 7.16/7.09 (d/d, 9.5 Hz, 4H, oxo-phenyl-amine/4-ethyl-phenyl), 3.87 (s, 2H, aryl-CH₂-aryl), 2.51 (qu, 7.5 Hz,2H, CH₂), 1.11 (t, 7.5 hz, 3H, CH₃); R_(f) (AcOEt/hexane = 2.1): 0.25;m.p. = 182.2- 183.6° C.. 14 CH₂ NH 4-Methyl, - M= = 317; ¹H-NMR (400MHz, DMSO-d₆): 8.54 (s, 1H, NH), 8.50 (s, 1H, NH), 8.42 (d, Hz, 6.5 Hz,2H, pyridinyl), 7.37/7.31 (d/d, 9.5 Hz, 4H, 4-methyl- phenyl,propyl-phenyl), 7.20 (d, 6.5 Hz, 2H, pyridinyl), 7.14/7.06 (d/d, 9.5 Hz,4H, oxo-phenyl- amine/4-methyl-phenyl), 3.87 (s, 2H, aryl-CH₂- aryl),2.20 (s, 3H, CH₃); R_(f) (AcOEt/hexane = 2.1): 0.35; m.p. = 197-198.5°C.. 15 CH₂ NH 3-CF₃, - M + H = 372.1; ¹H-NMR (400 MHz, DMSO-d₆): 9.14(s/broad, 1H, NH), 8.89 (s/broad, 1H, NH), 8.44 (d, 6.0 Hz, 2H,pyridinyl), 8.00 (s, 1H, phenyl-CF₃), 7.55 (d, 7.5 Hz, 1H, phenyl-CF₃),7.49 (t, 7.5 Hz, 1H, phenyl-CF₃), 7.40 (d, 8.0 Hz, 2H, phenyl-NH), 7.30(d, 7.5 Hz, 4H, phenyl-CF₃), 7.23 (d, 6.0 Hz, 2H, pyridinyl), 7.18 (d,8.0 Hz, 2H, phenyl-NH), 3.90 (s, 2H, aryl-CH₂-aryl); R_(f) (AcOEt/hexane= 2:1): 0.23; m.p. = 127-129° C..

Example 16 N-(4-pyridin-4-yl-oxy-phenyl)acetyl-(4-ethyl-phenyl)-amide

Aryl ether formation of 4-chloropyridine andN-(4-ethyl-phenyl)-2-(4-hydroxy-phenyl)-acetamide (Stage 16.1) isperformed according to the procedure of the synthesis of Stage 1.1:M+H=333.1; ¹H-NMR (400 MHz, DMSO-d₆): 10.10 (s, 1H, NH), 8.42 (d, Hz,6.5 Hz, 2H, pyridinyl), 7.48/7.41 (d/d, 9.5 Hz, 4H, phenyl), 6.81 (d,6.5 Hz, 2H, pyridinyl), 7.10 (d/d, 9.5 Hz, 4H, phenyl), 3.62 (s, 2H,aryl-CH₂-aryl), 2.52 (qu, 7.5 Hz, 2H, CH₂), 1.12 (t, 7.5 Hz, 3H, CH₃);R_(f) (AcOEt/hexane=2:1): 0.35; oil.

The starting material is prepared as follows:

Stage 16.1: N-(4-Ethyl-phenyl)-2-(4-hydroxy-phenyl)-acetamide

4-Hydroxyphenyl acetic acid (1.55 g, 10.2 mmol), 4-ethyl-phenylamine(1.28 ml, 10.3 mmol), TBTU (4.82 g, 15 mmol), and NMM (8.79 ml, 80 mmol)are stirred in DMF (30 ml) at rt for 5 h. The reaction mixture is takenup in AcOEt (0.2 L), washed with H₂O (40 ml, 2×) and brine (40 ml, 2×),dried (Na₂SO₄), concentrated under reduced pressure, and flashchromatographed (silica gel, 3.5×25 cm, AcOEt/hexane=1:2→2:3) giving thetitle compound of Stage 16.1 as a colorless solid (1.68 g, 6.59 mmol;66%) M+H=256.1; ¹H-NMR (400 MHz, DMSO-d₆): 10.0/9.24 (s/s, 1H, NH/OH),7.46 (d, 8.5 Hz, 2H, phenyl), 7.09 (d, 8.5 Hz, 4H, phenyl), 6.66 (d, 8.5Hz, 2H, phenyl), 3.47 (s, 2H, aryl-CH₂), 2.53 (qu, 7.5 Hz, 2H, CH₂),1.13 (t, 7.5 Hz, 3H, CH₃); R. (AcOEt/hexane=1:1): 0.66; m.p. =146-148°C.

Compounds of Examples 17 and 18 are synthesized analogously to thepreparation of the compound of Example 16 (data are enlisted on Table2). TABLE 2 Structures and analytical data of compounds of Examples17-18

Ex. R₁ Analytical data 17 4-Methyl M + H = 319.1; ¹H-NMR (400 MHz,DMSO-d₆): 10.10 (s, 1H, NH), 8.44 (d, Hz, 6.5 Hz, 2H, pyridinyl), 7.48(d, 9.5 Hz, 2H, phenyl-NH), 7.40 (d, 9.5 Hz, 2H, phenyl-O), 7.13 (d, 9.5Hz, 2H, phenyl-NH), 7.11 (d, 9.5 Hz, 2H, phenyl-O), 6.91 (d, 6.5 Hz, 2H,pyridinyl), 3.65 (s, 2H, aryl-CH₂-aryl), 2.24 (s, 3H, CH₃); R_(f)(AcOEt/hexane = 2:1): 0.12; m.p. = 157.5-158° C. 18 4-n-Propyl M + H =347.3; ¹H-NMR (400 MHz, DMSO-d₆): 10.12 (s, 1H, NH), 8.44 (d, Hz, 6.5Hz, 2H, pyridinyl), 7.50 (d, 9.5 Hz, 2H, phenyl), 7.46 (d, 9.5 Hz, 2H,phenyl), 7.18 (d, 9.5 Hz, 2H, phenyl), 7.13 (d, 9.5 Hz, 2H, phenyl),6.91 (d, 6.5 Hz, 2H, pyridinyl), 3.68 (s, 2H, aryl-CH₂-aryl), 2.49 (t,7.5 Hz, 2H, CH₂), 1.57 (sext, 7.5 Hz, 2H, CH₂), 0.87 (t, 7.5 Hz, 3H,CH₃); R_(f) (AcOEt/hexane = 1:3): 0.25; oil.

In Table 3, analytical data of compounds of the starting materials,Stage 17.1 and 18.1, are given.

Starting Materials: TABLE 3 Structures and analytical data of compoundsof Stages 17.1 and 18.1

Stage R₁ Analytical data 17.1 4-Methyl M + H = 241; ¹H-NMR (400 MHz,DMSO-d₆): 9.99/9.21 (s/s, 2H, NH/OH), 7.46 (d, 9.5 Hz, 2H, phenyl), 7.10(d, 9.5 Hz, 2H, phenyl), 7.08 (d, 9.5 Hz, 2H, phenyl), 6.68 (d, 9.5 Hz,2H, phenyl), 3.48 (s, 2H, aryl-CH₂-aryl), 3.40 (s, 3H, CH₃); R_(f)(AcOEt/hexane = 1:2): 0.24. 18.1 4-Propyl M − H = 268.2; ¹H-NMR (400MHz, DMSO-d₆): 9.99/9.22 (s/s, 2H, NH/OH), 7.46 (d, 9.5 Hz, 2H, phenyl),7.10 (d, 9.5 Hz, 2H, phenyl), 7.08 (d, 9.5 Hz, 2H, phenyl), 6.68 (d, 9.5Hz, 2H, phenyl), 3.46 (s, 2H, aryl-CH₂-aryl), 2.47 (t, 7.5 Hz, 2H, CH₂),1.53 (sext, 7.5 Hz, 2H, CH₂), 0.83 (t, 7.5 Hz, 3H, CH₃); R_(f)(AcOEt/hexane = 1:1): 0.57.

Example 195(4-pyridyloxy)-N-(3-trifluoromethyl-phenyl)amino-carbonyl-2,3-dihydroindole

After stirring a solution of 3-(trifuoromethyl)-phenyl isocyanate (0.348ml, 2.45 mmol), 5-(pyridin-4-yl-oxy)-2,3-dihydroindole (Stage 19.1; 0.13g, 0.613 mmol), pyridine (0.104 ml, 1.29 mmol) in THF (4 ml) is stirredat rt for 4 d. The reaction mixture is concentrated under reducedpressure and flash chromatographed (silica gel, 2.5×18 cm,acetone/CH₂Cl₂=1:3) to give compound of Example 19 as a beige solid:M+H=400.1; ¹H-NMR (400 MHz, DMSO-d₆): 8.87 (s, 1H, NH), 8.41 (d, Hz, 6.5Hz, 2H, pyridinyl), 8.02 (s, 1H, 3-CF₃-phenyl), 9.5 Hz, H, indoline),7.86 (d, 8.0 Hz, H, —CF₃-phenyl), 7.53 (t, 8.0 Hz, 1H, 3-CF₃-phenyl),7.36 (d, 8.0 Hz, H, CF₃-phenyl), 7.07 (d, 3.5 Hz, 1H, indoline), 6.94(dd, 9.5 Hz, 3.5 Hz, 1H, indoline), 6.84 (d, 6.5 Hz, 2H, pyridinyl, 4.19(t, 8.0 Hz, 2H, CH₂), 3.19 (t, 8.0 Hz, 2H, CH₂);R_(f)(acetone/H₂Cl₂=1:3): 0.22; m.p.=171-172.5° C.

The starting materials are prepared as follows:

Stage 19.1: 5-(pyridin-4-yl-oxy)-2,3-dihydroindole

During 5 min, NaBH₃CN (315 mg, 4.76 mmol) is added to a solution of5-pyridin-4-yl-oxy-indoline (Stage 19.2; 0.2 g, 0.95 mmol) in AcOH (4.75ml) at 0° C. After stirring for 4 h at rt, ice (10 g) is added and theAcOH is evaporated under reduced pressure. The resulting oil is adjustedto pH=11 by adding 1 N NaOH, extracted with ether (20 ml, 3×). Thecombined ether phases are washed with 1 N NaOH (10 ml), H₂O (10 ml, 2×),and brine (10 ml, 2×), dried (MgSO₄), concentrated under reducedpressure, and flash chromatographed (silica gel, 2.5×18 cm;acetone/CH₂Cl₂=1:3) to give the title compound of Stage 19.1 as a palesolid: M+H=213.1; ¹H-NMR (400 MHz, DMSO-d₆): 8.37 (d, Hz, 6.5 Hz, 2H,pyridinyl), 6.82 (d, 3.5 Hz, 1H, indoline), 6.80 (d, 6.5 Hz, 2H,pyridinyl), 6.67 (dd, 9.5 Hz, 3.5 Hz, 1H, indoline), 6.50 (d, 9.5 Hz, H,indoline), 5.54 (s/broad, 1H, NH), 3.44 (t, 8.0 Hz, 2H, CH₂), 2.92 (t,8.0 Hz, 2H, CH₂); R_(f) (acetone/H₂Cl₂=1:3): 0.22; m.p.=115.5-117.5° C.

Stage 19.2: 5-pyridin-4-yl-oxyindoline

The title compound of Stage 19.2 is synthesized according to theprocedure of the preparation of the compound of Stage 1.1: M+H=211.0;¹H-NMR (400 MHz, DMSO-d₆): 8.37 (d, Hz, 6.5 Hz, 2H, pyridinyl), 7.47 (d,9.5 Hz, 1H, indole-H7), 7.44 (d, 2.0 Hz, 1H, indole-H2), 7.34 (d, 2.0Hz, 1H, indole-H5), 6.84 (d, 9.5 Hz, H, Indole-H8), 6.83 (d, Hz, 6.5 Hz,2H, pyridinyl), 6.42 (d, 2.0 Hz, 1H, indole-H3); R_(f)(acetone/H₂Cl₂=1:3): 0.38; m.p.=176-177.5° C.

Example 205-(4-pyridyl-oxy)-N-(3-trifluoromethyl-phenyl)amino-carbonyl-1,2,3,4-tetrahydroquinoline

The title compound of Example 20 is prepared analogously to thesynthesis of the compound of Example 19 via urea formation with6-(pyridin-4-yl-oxy)-1,2,3,4-tetrahydroquinoline (Stage 20.1):M+H=414.0; ¹H-NMR (400 MHz, DMSO-d₆): 9.19 (s, 1H, NH), 8.42 (d, Hz, 6.5Hz, 2H, pyridinyl), 7.94 (s, 1H, 3-CF₃-phenyl), 7.73 (d, 9.5 Hz, H,indoline), 7.45 (t, 8.0 Hz, 1H, 3-CF₃-phenyl ), 7.43 (s, 1H, 1H,dihydroquinole-H8), 7.29 (d, 8.0 Hz, H, CF₃-phenyl), 6.98 (d, 3.5 Hz,1H, dihydroquinole-H5), 6.93 (dd, 9.5 Hz, 3.5 Hz, 1H,dihydroquinole-H7), 6.89 (d, 6.5 Hz, 2H, pyridinyl), 3.75 (t, 8.0 Hz,2H, CH₂), 2.75 (t, 8.0 Hz, 2H, CH₂), 1.90 (sext, 8.0 Hz, 2H, CH₂); R_(f)(acetone/CH₂Cl₂=1:3): 0.33; m.p.=185.5-188° C.

The starting materials are prepared as follows:

Stage 20.1: 6-(pyridin-4-yl-oxy)-1,2,3,4-tetrahydroquinoline

The title compound is prepared via reduction of the correspondingquinoline (Stage 20.2) analogously to the synthesis of the compound ofExample 19.1: M+H=227.1; ¹H-NMR (400 MHz, DMSO-d₆): 8.37 (d, Hz, 6.5 Hz,2H, pyridinyl), 6.78 (d, 6.5 Hz, 2H, pyridinyl), 6.66 (m, 2H,tetrahydroquinoline), 6.46 (d, 9.5 Hz, 3.5 Hz, 1H, tetrahydroquinoline),5.74 (s/broad, 1H, NH), 3.17 (t, 8.0 Hz, 2H, CH₂), 2.65 (t, 8.0 Hz, 2H,CH₂) 1.74 (sext, 8.0 Hz, 2H, CH₂); R_(f) (acetone/H₂Cl₂=1:3): 0.26;m.p.=117-121.5° C.

Stage 20.2: 6-(pyridin-4-yl-oxy)-quinoline

The compound of Stage 20.2 is synthesized according to the procedure ofthe preparation of the compound of Stage 19.2: M+H=211.0; ¹H-NMR (400MHz, DMSO-d₆): 8.87 (dd, 3.5 Hz, 2.0 Hz, 1H, quinoline-H1), 8.48 (d, 6.5Hz, 2H, pyridinyl), 8.35 (dd, 7.7 Hz, 2.0 Hz, 1H, quinoline-H3), 8.11(d, 9.0 Hz, 1H, quinoline-H8), 7.75 (d, 3.0 Hz, 1H, quinoline-H5), 7.59(dd, 9.0 Hz, 3.0 Hz, H, quinoline-H7), 7.54 (dd, 7.7 Hz, 3.5 Hz, 1H,quinoline-H2), 7.03 (d, Hz, 6.5 Hz, 2H, pyridinyl); R_(f)(acetone/H₂Cl₂=1:3): 0.26.

Example 21N-(4-(6-Chloropyrimidin-4-yl)-oxyphenyl)-N′-(3-trifluoromethylphenyl)-urea

After stirring 3-trifluoromethyl-phenyl isocyanate (412 mg, 2.2 mmol),4-(6-chloro-pyrimidin-4-yl-oxy)-aniline (Stage 21.1; 0.25 g, 1.1 mmol),and pyridine (0.18 ml), dissolved in THF (3 ml) overnight, the reactionsolution is concentrated under reduced pressure and flashchromatographed (silica gel, 2.5×17 cm; acetone/CH₂Cl₂=5:95→1:9) to givecompound of Example 21 as a colorless solid: M+H=408.9/410.9; ¹H-NMR(400 MHz, DMSO-d₆): 9.07 (s, 1H, NH), 8.89 (s, 1H, NH), 8.63 (d, 2.0 Hz,1H, pyridinyl), 8.01 (s, 1H, 3-CF₃-phenyl), 7.57 (d/broad, 8.0 Hz, 1H,CF₃-phenyl), 7.52 (d, 9.5 Hz, 2H, oxo-phenyl-amine), 7.50 (m, 1H,3-CF₃-phenyl), 7.32 (d, 2.0 Hz, 1H, pyridinyl), 7.29 (d/broad, 8.0 Hz,1H, —CF₃-phenyl), 7.15 (d, 9.5 Hz, 2H, oxo-phenyl-amine), (d, 6.5 Hz,2H, pyridinyl); R_(f) (acetone/CH₂Cl₂=1:9): 0.54; m.p.=187.4-189.7° C.

The starting materials are prepared as follows:

Stage 21.1: 4-(6-Chloro-pyrimidin-4-yl-oxy)-aniline

4-Chloro-6(4-nitro-phenoxy)-pyrimidine (Stage 21.2; 3.6 g, 14.3 mmol)dissolved in MeOH (250 ml) is hydrogenated in the presence of Raney-Ni(3 g) at 40° C. for 3 d. The reaction solution is filtered, concentratedunder reduced pressure and crystallized from AcOEt/hexane to give thetitle compound of Stage 21.1: M+H=222/224; ¹H-NMR (400 MHz, DMSO-d₆):8.62 (s, 1H), 7.13 (s, 1H), 6.83 (d, 9 Hz, 2H, phenyl), 6.56 (d, 9 Hz,2H, phenyl), 5.12 (s, 2H, NH₂); m.p.=135.5-138.1° C.

Stage 21.2: 4-Chloro-6-(4-nitro-phenoxy)-pyrimidine

4-Nitrophenol (2.8 g, 20.1 mmol), 2,4-dichloro-pyrimidine (3 g, 20.1mmol), NaOH (0.8 g, 20.1 mmol) dissolved in H₂O/acetone (80 ml; 1:1) arestirred at 60-65° C. for 1 h. The reaction solution is concentratedunder reduced pressure and flash chromatographed (silica gel, 4.5×22 cm,AcOEt/hexane=1:4) to give the title compound of Stage 21.2 as acolorless solid: M+H=252/254; ¹H-NMR (400 MHz, DMSO-d₆): 8.67 (s, 1H,pyrimidinyl), 8.34 (d, 9 Hz, 2H, phenyl), 7.58 (d, 9 Hz, 2H, phenyl),7.53 (s, 1H, pyrimidinyl); R_(f) (AcOEt/hexane=1:1): 0.16;m.p.=125.4-126.6° C.

Example 22N-(4-(4-(4-hydroxyphenylamino)-pyrimidin-6-yl)-oxyphenyl)-N′-(3-trifluoromethylphenyl)-urea

1-(4-{6-[4-(tert-Butyl-dimethyl-silyloyloxy)-phenylamino]-pyrimidin-4-yl-oxy)-phenyl)-3-(3-trifluoromethyl-phenyl)urea(Stage 22.1; 0.7 g, 1.17 mmol) is dissolved in HF/pyridine (70%, 1 ml)and MeCN/THF (4 ml/2 ml) at 0° C. After stirring for 3 h at rt, thereaction mixture is neutralized by adding phosphate buffer (pH=7, 10 mL)and the product is taken up in AcOEt (10 ml, 2×), dried (MgSO₄), flashchromatographed (silica gel, 2.5×17 cm, MeOH/CH₂Cl₂=1:9) to give thetitle compound of Example 22 as a colorless solid: M+H=481.9; ¹H-NMR(400 MHz, DMSO-d₆): 9.23/9.21 (s/s, 2H, NH, OH), 9.10/8.91 (s/s, 2H,NH-urea,), 8.23 (s, 1H, pyrimidinyl), 8.01 (s, 1H, CF₃-phenyl), 7.58 (d,8.8 Hz, 1H, CF3-phenyl), 7.51 (m, 3H, phenyl-urea/CF3-phenyl), 7.26 (m,3H, phenyl-OH/CF3-phenyl), 7.10 (d, 8.8 Hz, 2H, phenyl-urea), 6.71 (d,8.8 Hz, 2H, phenyl-OH), 5.90 (s, 1H, pyrimidinyl); R_(f)(MeOH/CH₂Cl₂=1:9)=0.29 (silica gel); m.p.=142° C. (decomp.).

The starting materials are prepared as follows:

Stage 22.1:1-(4-{6-[4-(tert-Butyl-dimethyl-silyloyloxy)-phenylamino]-pyrimidin-4-yl-oxy}-phenyl)-3-(3-trifluoromethyl-phenyl)urea

After stirring[6-(4-amino-phenoxy)-pyrimidin-4-yl][4-(tert-butyl-dimethyl-silyloxy)-phenyl]-amine(Stage 22.2; 1 g, 2.45 mmol), 3-trifluoromethyl-phenyl-isocyanate (916mg, 4.9 mmol), NEt₃ (0.682 ml, 4.9 mmol) dissolved in DMF (6 ml) for 1h, the reaction mixture is concentrated under reduced pressure and flashchromatographed (silica gel, 2.5×19 cm, AcOEt/hexane=1:2→2:1) to givethe title compound of Stage 22.1 as a colorless solid: M+H=595.9; ¹H-NMR(400 MHz, DMSO-d₆): 9.3619.0718.85 (s/s/s, 3H, NH-urea, NH), 8.24 (s,1H, pyrimidinyl), 8.02 (s, 1H, CF₃-phenyl), 7.57 (d, 8.8 Hz, 1H,CF₃-phenyl), 7.50 (m, 3H, phenyl-urea/CF3-phenyl), 7.39 (m, 3H,phenyl-OTBS/CF₃-phenyl), 7.10 (d, 8.8 Hz, 2H, phenyl-urea), 6.78 (d, 8.8Hz, 2H, phenyl-OTBS), 5.92 (s, 1H, pyrimidinyl), 0.90 (s, 9H, TBS), 0.18(s, 6H, TBS).

Stage 22.2:[6-(4-Amino-phenoxy)-pyrimidin-4-yl][4-(tert-butyl-dimethyl-silyloxy)-phenyl]-amine

[4-(tert-Butyl-dimethyl-silyloxy)-phenyl]-[6-(4-nitro-phenoxy)-pyrimidin-4-yl]-amine(Stage 22.3; 1.8 g, 4.1 mmol) is reduced by means of Raney-Ni (0.4 g) inEtOH/THF (35/15 ml) during 3 h and purified by flash chromatography(silica gel, 3.0×18 cm, AcOEt/hexane=1:1→4:1) to give compound of Stage22.2 as a colorless solid: M+H=409.1; ¹H-NMR (400 MHz, DMSO-d₆): 9.22(s, 1H, NH), 8.20 (s, 1H, pyrimidinyl), 7.37 (d, 8.8 Hz, 2H,phenyl-OTBS), 6.77 (d, 8.8 Hz, 2H, phenyl-NH₂), 6.70 (d, 8.8 Hz, 2H,phenyl-OTBS), 6.55 (8.8 Hz 2H, phenyl-NH₂), 5.79 (s, 1H, pyrimidinyl),5.02 (s, 2H, NH₂), 0.90 (s, 9H, TBS), 0.12 (s, 6H, TBS); R_(f)(AcOEt/hexane=2:1): 0.22.

Stage 22.3:[4-(tert-Butyl-dimethyl-silyloxy)-phenyl]-[6-(4-nitro-phenoxy)-pyrimidin-4-yl]l-amine

4-[6-(4-Nitro-phenoxy)pyrimidin-4-ylamino]-phenol (Stage 22.4; 1.5 g,4.63 mmol), tert-butyl-dimetylsilyl chloride (1.39 g, 9.26 mmol), NEt₃(1.29 ml, 9.26 mmol) dissolved in DMF (20 ml) are stirred for 3.5 h.After concentrating the reaction mixture under reduced pressure anddissolving in phosphate buffer (50 ml, pH=7), the product is extractedby means of AcOEt (10 ml) and purified by flash chromatography (silicagel, 3.0×17 cm, AcOEt/hexane=1:1→4:1) to give the title compoundcompound of Stage 22.3 as a colorless solid: M+H=439.0; ¹H-NMR (400 MHz,DMSO-d₆): 9.56 (s, 1H, NH), 8.28 (m, 3H, pyrimidinyl, phenyl-NO₂), 7.40(m, 4H, phenyl-OTBS, phenyl-NO₂), 6.81 (d, 8.8 Hz, 2H, phenyl-OTBS, 6.20(s, 1H, pyrimidinyl), 0.93 (s, 9H, TBS), 0.18 (s, 6H, TBS).

Stage 22.4: 4-[6-(4-Nitro-phenoxy)-pyrimidin-4-ylamino]-phenol

4-Chloro-6-(4nitro-phenoxy)pyrimidine (Stage 22.5; 3 g, 11.9 mmol),4-nitrophenol (1.95 g, 17.9 mmol), and diisopropylethylamine (DIPEA)(3.04 ml, 179 mmol) dissolved in 2-propanol (50 ml) are stirred at 85°C. for 18 h. After concentrating the reaction mixture under reducedpressure, the product precipitates as a colorless fine solid: M+H=245.0;¹H-NMR (400 MHz, DMSO-d₆): 9.40/9.25 (s/s, 2H, NH/OH), 8.28 (d, 7.5 Hz,2H, phenyl-NO₂), 8.26 (s, 1H, pyrimidinyl), 7.40 (d, 7.5 Hz, 2H,phenyl-NO₂), 7.24 (d, 8.0 Hz, 2H, phenyl-OH), 6.77 (d, 8.0 Hz, 2H,phenyl-OH), 6.15 (s, 1H, pyrimidinyl); R_(f) (AcOEt/hexane=2:1): 0.48.

Stage 22.5: 4-Chloro-6-(4-nitro-phenoxy)-pyrimidine

4,6-Dicholoropyrimidine (3 g, 20 mmol), 4-nitrophenol (2.8 g, 20 mmol),NaOH (0.8 g, 20 mmol) dissolved in H₂O/acetone (25/25 ml) are stirred at45° C. for 22 h. The precipitated product is isolated by filtration:M+H=252.0/254.0; ¹H-NMR (400 MHz, DMSO-d₆): 9.67 (s, 1H, pyrimidinyl),9.32 (d, 8.2 Hz, 2H, phenyl), 7.58 (s, 1H, pyrimidinyl), 7.56 (d, 8.2Hz, 2H, phenyl); R_(f) (AcOEt/hexane=1:1): 0.20.

In accordance with the methods described hereinbefore, the followingcompounds, with the substituents given in Table 4, are prepared: TABLE 4

Ex. Q R₁ R₂ 23

4-phenyl 3-trifluoromethyl 24

3-trifluoromethyl 25

3-methoxy 4,5-dimethoxy 26

3-methoxy 4-phenyl 27

3-methoxy 4-O—CH₂—CF₃ 28

3-methoxy

29

H

30

3-trifluoromethyl H 31

3-trifluoromethyl H 32

3-trifluoromethyl 4-(2,2,2-trifluoroethoxy) 33

3-trifluoromethyl H 34

3-trifluoromethyl H

Example 23

M+H=450.0; ¹H-NMR (400 MHz, DMSO-d₆): 9.15 (s, 1H, NH), 8.95 (s, 1H,NH), 8.44 (d, 6.5 Hz, 2H, pyridinyl), 8.09 (s, 1H, CF₃/phenyl-phenyl),7.67 (d, 6.5 Hz, 1H, CF₃/phenyl-phenyl), 7.57 (d, 8.5 Hz, 2H,oxo-phenyl-amine), 7.41 (M, 3H, phenyl), 7.31 (t, 7.5 Hz, 2H, phenyl),7.15 (d, 8.5 Hz, 2H, oxo-phenyl-amine), 6.90 (m, 4H,pyridinyl/piperidinyl-phenyl), 2.99 (t, 6.5 Hz, 4H, CH₂, piperidinyl),1.60 (t/broad, 4H, CH₂, piperidinyl), 1.47 (m/broad, 1H, piperidinyl);R_(f) (acetone/CH₂Cl₂=1:3): 0.22; m.p: 120° C. (decomp.).

Example 24

M+H=458.9; ¹H-NMR (400 MHz, DMSO-d₆): 8.97 (s, 1H, NH), 8.85 (s, 1H,NH), 8.43 (d, Hz, 6.5 Hz, 2H, pyridinyl), 7.89 (s, 1H, 3-CF₃-phenyl),7.59 (d, 9.5 Hz, 1H, 3-CF₃-phenyl), 7.54 (d, 8.0 Hz, 2H, oxo-phenyl),7.49 (t, 8.0 Hz, 1H, 3-CF₃-phenyl), 7.11 (d, 8.0 Hz, 2H, oxo-phenyl),6.84 (d, 6.5 Hz, 2H, pyridinyl), 3.68 (s/broad, 4H, morpholinyl), 2.78(s/broad, 4H, morpholinyl); R_(f) (MeOH/CH₂Cl₂=1:19): 0.11; m.p.>120° C.(decomp.).

Example 25

M+H=396.0; ¹H-NMR (400 MHz, DMSO-d₆): 8.73 (s, 1H, NH), 8.62 (s, 1H,NH), 8.42 (d/broad, 6.5 Hz, 2H, pyridinyl), 7.56 (d, 9.5 Hz, 2H,oxo-phenyl-amine), 7.10 (d, 9.5 Hz, 2H, oxo-phenyl-amine), 6.84 (d, 6.5Hz, 2H, pyridinyl), 6.77 (s, 2H, trimethoxy-phenyl), 3.73 (s, 6H, CH₃)3.32 (s, 3H, CH₃); R_(f) (acetone/CH₂Cl₂=1:3): 0.26; m.p: 179° C.(decomp.).

Example 26

Is synthesized according to the synthesis of compound of Example 1starting from 2-methoxy-biphenyl-4-ylamine (Stage 26.1): M+H=412.0;¹H-NMR (400 MHz, DMSO-d₆): 8.81/8.79 (s/s, 2H, NH), 8.41 (d, 6.5 Hz, 2H,pyridinyl), 7.56 (d, 9.5 Hz, 2H, oxo-phenyl-amine), 7.44 (d, 7.0 Hz, 2H,phenyl), 7.36 (t/s, 7.0 Hz, 3H, phenyl/phenyl-OMe), 7.24 (t, 7.0 Hz, 1H,phenyl), 7.18 (d, 8.5 Hz, 1H, phenyl-OMe), 7.09 (d, 9.5 Hz, 2H,oxo-phenyl-amine), 7.01 (d, 8.5 Hz, 1H, phenyl-OMe), 6.84 (d, 6.5 Hz,2H, pyridinyl), 3.73 (s, 6H, CH₃) 3.73 (s, 3H, CH₃); R_(f)MeOH/CH₂Cl₂=5:95): 0.31.

Stage 26.1

2-Methoxy-4-nitro-biphenyl (Stage 26.2) (867 mg, 3.78 mmol) dissolved inTHF/EtOH (1:5, 20 mL) is hydrogenated in the presence of Pd/C (100 mg)at rt for 30 min. After filtering off the catalyst and washing with EtOH(5 mL), the reaction solution is evaporated under reduced pressure togive compound of Stage 26.1 as colorless oil: M+H=200.0; ¹H-NMR (400MHz, DMSO-d₆): 7.37 (d, 7.0 Hz, 2H, phenyl), 7.31 (t, 7.0 Hz, 2H,phenyl), 7.17 (t, 7.0 Hz, 1H, phenyl), 6.83 (d, 8.5 Hz, 1H, phenyl-OMe),6.30 (s, 1H, phenyl-OMe), 5.21 (s, 2H, NH₂), 3.64 (s, 3H OMe); HPLC(System 1): 3.92 min.

Stage 26.2

To 1-bromo-2-methoxy-4-nitro-benzene (1.0 g, 4.3 mmol) dissolved in DMF(37 mL), under Ar-atmosphere, phenyl-boronic acid (578 mg, 4.74 mmol),(AcO)₂Pd (48 mg, 0.215 mmol), tri-o-tolyl-phosphane (131 mg, 0.431mmol), and K₂CO₃ (1M, 11 mL, 10.77 mmol) are added. After stirring at120° C. for 1 h, the reaction solution is filtered over Hyflo,concentrated under reduced pressure, partitioned between AcOEt and H₂O(100 mL/100 mL), and extracted with AcOEt (50 mL, 2×). The combinedorganic phases are washed with H₂O (50 mL), dried (Na₂SO₄), concentratedunder reduced pressure, and flash chromatographed (silica gel, 4.5×22cm, hexane/AcOEt=9:1) to give compound of Stage 26.2 as colorless oil:M+H=231.0; ¹H-NMR (400 MHz, DMSO-d₆): 7.92 (d, 7.0 Hz, 1H), 7.88 (s,1H), 7.57 (d, 7.0 Hz, 1H), 7.54 (d, 7.0 Hz, 1H), 7.49 (t, 7.0 Hz, 3H),7.42 (d, 7.0 Hz, 1H), 3.92 (s, 3H OMe); HPLC (System 1): 7.06 min.

Example 27

M+H=434.0; ¹H-NMR (400 MHz, DMSO-d₆): 8.74 (s, 1H, NH), 8.62 (s, 1H,NH), 8.41 (d, Hz, 6.5 Hz, 2H, pyridinyl), 7.52 (d, 8.5 Hz, 2H,oxo-phenyl-amino), 7.29 (s, 1H, MeO-phenyl), 7.09 (d, 8.0 Hz, 2H,oxo-phenyl-amino), 6.97 (d, 8.5 Hz, 1H, MeO-phenyl), 6.94 (d, 6.5 Hz,2H, pyridinyl), 3.77 (s, 3H, MeO); R_(f) (MeOH/CH₂Cl₂=5:95): 0.27.

Example 28

Is synthesized according to the synthesis of compound of Example 1starting from 3-methoxy-4-piperidin-1-yl-phenylamine (Stage 28.1):M+H=419.1; ¹H-NMR (400 MHz, DMSO-d₆): 8.68/8.51 (s/s, 2H, NH), 8.39 (d,6.5 Hz, 2H, pyridinyl), 7.52 (d, 9.5 Hz, 2H, oxo-phenyl-amine), 7.17 (s,1H, phenyl-OMe), 7.09 (d, 9.5 Hz, 2H, oxo-phenyl-amine), 6.85 (d, 6.5Hz, 2H, pyridinyl), 6.83/6.78 (d/d, 8.0 Hz, 4H, phenyl-OMe), 3.74 (s,6H, O—CH₃) 2.80/1.60 (m/m, 4H/4H, CH₂-piperidinyl), 1.48 (m, 2H,CH₂-piperidinyl); R_(f) MeOH/CH₂Cl₂=1:9): 0.42.

Stage 28.1

1-(2-Methoxy-4-nitro-phenyl)-piperidine (Stage 28.2) (3.9 g, 16.5 mmol)dissolved in EtOH (20 mL) is hydrogenated in the presence of Pd/C (100mg) at rt for 3 h. After filtering off the catalyst and washing withEtOH (5 mL), the reaction solution is evaporated under reduced pressureto give compound of Stage 28.1 as colorless oil: M+H=207.1; ¹H-NMR (400MHz, DMSO-d₆): 6.58 (d, 8.0 Hz, 1H, phenyl), 6.19 (s, 1H, phenyl), 6.03(d, 8.0 Hz, 1H, phenyl), 4.64 (s, 2H, NH₂), 3.66 (s, 6H, O—CH₃)2.91/1.57 (m/m, 4H/4H, CH₂-piperidinyl), 1.42 (m, 2H, CH₂-piperidinyl);HPLC (System 1): 4.36 min.

Stage 28.2

1-Bromo-2-methoxy-4-nitro-benzene (5 g, 21.5 mmol) and piperidine (8.5mL, 86.2 mmol) are stirred under reflux for 4 h. After taking up in H₂O(80 mL), the reaction solution is extracted with CH₂Cl₂ (80 mL, 2×). Thecombined organic phases are dried (Na₂SO₄), concentrated under reducedpressure, and flash chromatographed (silica gel, 5.5×22 cm,hexane/AcOEt=9:1) to give compound of Stage 28.2 as colorless solid:M+H=237.1; ¹H-NMR (400 MHz, DMSO-d₆): 7.80 (d, 8.0 Hz, 1H, phenyl), 7.63(s, 1H, phenyl), 6.97 (d, 8.0 Hz, 1H, phenyl), 4.64 (s, 2H, NH₂), 3.88(s, 6H, O—CH₃), 3.16/1.61 (m/m, 4H/4H, CH₂-piperidinyl), 1.58 (m, 2H,CH₂-piperidinyl); HPLC (System 1): 4.90 min.

Example 29

M+H=389.2; ¹H-NMR (400 MHz, DMSO-d₆): 8.64 (s, 1H, NH), 8.21 (d, 6.5 Hz,2H, pyridinyl), 8.38 (s, 1H, NH), 7.51 (d, 9.5 Hz, 2H,oxo-phenyl-amine), 7.23 (s, 1H, phenyl-piperidinyl), 7.07 (d, 9.5 Hz,2H, oxo-phenyl-amine), 6.86 (m, 4H, pyridinyl/phenyl-pyridinyl),2.99/1.60 (m/m, 4H/4H, CH₂piperidinyl), 1.48 (m, 2H, CH₂-piperidinyl);R_(f) (acetone/CH₂Cl₂=3:7): 0.14.

Example 30

M+H=387.9; ¹H-NMR (400 MHz, DMSO-d₆): 9.07 (s, 1H, NH), 8.85 (s, 1H,NH), 8.29 (d, Hz, 6.5 Hz, 1H, pyridinyl), 8.01 (s, 1H, 3-CF₃-phenyl,7.58 (d, 9.5 Hz, 2H, oxo-phenyl-amine), 7.50 (d, 8 Hz, 1H, oxo-phenyl),7.53 (t, 8.0 Hz, 1H, 3-CF₃-phenyl, 7.30 (d, 8.0 Hz, 1H, 3-CF₃-phenyl),7.04 (d, 9.5 Hz, 2H, oxo-phenyl, 6.73 (d, 3.5 Hz, 1H, pyridinyl), 6.69(dd, 3.5 Hz, 6.5 Hz, 1H, pyridinyl), 2.18 (s, 3H, CH₃); R_(f)(acetone/CH₂Cl₂=1:3): 0.19; m.p=160-163° C. (decomp.).

Example 31

Is synthesized in analogy to the preparation of compound of Example 22:M+H=482.4; ¹H-NMR (400 MHz, DMSO-d₆): 10.25/9.98 (s/s, 2H, NH/OH),9.2718.99 (s/s, 2H, NH-urea,), 8.26 (d, 6.5 Hz, 1H, pyrimidinyl), 7.96(s, 1H, CF₃-phenyl), 7.70 (m, 2H, CF₃-phenyl), 7.53 (d, 8 Hz, 2H,oxo-phenyl-urea), 7.44 (d, 7.0 Hz, 1H, CF₃-phenyl), 7.30 (d, 8.0 Hz, 2H,hydroxy-phenyl-amino), 7.18 (d, 8.0 Hz, 2H, oxo-phenyl-urea), 6.58 (d,8-0 Hz, 2H, hydroxy-phenyl-amino), 6.30 (d, 6.5 Hz, 1H, pyrimidinyl);HPLC (System 1): 6.55 min.

Example 32

Is synthesized in analogy to the preparation of compound of Example 22:M+H=579.8; ¹H-NMR (400 MHz, DMSO-d₆): 9.25/9.23 (s/s, 2H, NH, OH),8.94/8.88 (s/s, 2H, NH-urea,), 8.23 (s, 1H, pyrimidinyl), 7.94 (d, 2 Hz,1H, CF₃—CH₂—O—/CF₃-phenyl), 7.65 (dd, 8.5 Hz, 2 Hz, 1H,CF₃—CH₂—O—/CF₃-phenyl), 7.55 (d, 9.0 Hz, 2H, oxo-phenyl-amino), 7.36 (d,8.5 Hz, 1H, CF₃—CH₂—O—/CF₃-phenyl), 7.29 (d, 9.0 Hz, 2H,oxo-phenyl-urea), 7.10 (d, 8.8 Hz, 2H, oxo-phenyl-urea), 6.75 (d, 9.0Hz, 2H, oxo-phenyl-amino), 5.93 (s, 1H, pyrimidinyl), 4.38 (q, 8.4 Hz,2H, CH₂); R_(f) (NH₃/MeOH/CH₂Cl₂=0.01:1:9): 0.27.

Example 33

Compound of Example 2 (29 mg, 0.078 mmol) and m-chloro-perbenzoic acid(28.9 mg, 0.17 mmol) are stirred in CH₂Cl₂/CHCl₃ (1:1; 3 mL) for 3 h at45° C. Separation is performed by preparative TLC (2 plates, 20×20 cm,MeOH/CH₂Cl₂=1:4): M+H=390.0; ¹H-NMR (400 MHz, DMSO-d₆): 9.39 (s, 1H,NH), 9.21 (s, 1H, NH), 8.11 (d, 9.0 Hz, 2H, pyridinyl), 8.01 (s, 1H,CF₃-phenyl), 7.59 (d, 8.5 Hz, 1H CF₃-phenyl), 7.54 (d, 10.0 Hz, 2H,oxo-phenyl), 7.49 (t, 8.5 Hz, 1H, CF₃-phenyl), 7.28 (d, 8.5 Hz, 1H,CF₃-phenyl), 7.09 (d, 10.0 Hz, 2H, oxo-phenyl), 6.93 (d, 9.0 Hz, 1H,pyridinyl); R_(f) (MeOH/CH₂Cl₂=1:9): 0.19.

Example 34

Is preapared according to the procedure of the synthesis of compound ofExample 22: M+H=525.7; ¹H-NMR (400 MHz, DMSO-d₆): 9.13/8.90 (s/s, 2H,NH-urea), 8.22 (s, 1H, pyrimidinyl), 7.98 (s, 1H, CF₃-phenyl), 7.56 (d,7.5 Hz, 1H, CF₃-phenyl), 7.47 (t, 7.5 Hz, 1H, CF₃-phenyl), 7.42 (d, 8.3Hz, 2H, oxo-pheny-urea), 7.29 (d, 7.5 Hz, 1H, CF₃-phenyl), 7.13 (d, 8.8Hz, 2H, oxo-phenyl-amino), 6.96 (d, 8.3 Hz, 2H, oxo-phenyl-urea), 5.87(s, 1H, pyrimidinyl), 5.42 (s, 1H, NH), 3.91/2.83 (t/t/broad, 4H, CH₂).

Example 35N-[4-(pyridin-4-yl-oxy)-3-chloro-phenyl]-N′-(3-trifluoromethyl-phenyl)-urea

Triphosgene (91 mg, 0.30 mmol) dissolved in CH₂Cl₂ (9 mL) is added to asolution of 3-chloro-4-(pyridin-4-yloxy)-phenylamine (Stage 35.1) (0.2g, 0.906 mmol) and NEt₃ (0.11 mL, 1.5 mmol) in CH₂Cl₂ (4.5 mL) during 4min at 0° C. After stirring the reaction solution for 10 min at rt, asolution of 3-trifluoromethyl-phenylamine (0.114 mL, 0.906 mmol) andNEt₃ (0.11 mL, 1.5 mmol) in CH₂Cl₂ (4.5 mL) is added. After stirring for4.5 h, the rection solution is poured onto concentrated NaHCO₃ solution,and extracted with CH₂Cl₂ (25 mL, 5×). The combined organic phases arewashed with brine (20 mL), died (MgSO₄), concentrated under reducedpressure, and fklash chromatographed (silica gel, 3.5×35 cm;AcOEt/hexane=2:1→3:1) to give compound of Example 35 as slightlyyellowish solid (301 mg, 0.74 mmol; 81%), M+H=408.0; ¹H-NMR (400 MHz,DMSO-d₆): 9.20/9.11 (s/s, 2H, NH), 8.45 (d, 6.5 Hz, 2H, pyrimidinyl),8.01 (s, 1H, CF₃-phenyl), 7.90 (s, 1H, Cl-phenyl), 7.60 (d, 7.5 Hz, 1H,CH₃-phenyl, 7.53 (t, 7.5 Hz, 1H, CF₃-phenyl), 7.41 (d, 8.5 Hz, 1H,Cl-phenyl), 7.33 (m, 2H, phenyl-Cl/CF₃-phenyl), 6.88 (s, 2H,pyrimidinyl); HPLC (System 1): 5.43 min.

Stage 35.1

Is prepared according to the synthesis of compound of Stage 1.1:M+H=221.0; ¹H-NMR (400 MHz, DMSO-d₆): 8.38 (d, 6.5 Hz, 2H, pyrimidinyl),6.98 (d, 8.5 Hz, 1H Cl-phenyl), 6.77 (d, 7.0 Hz, 2H, Cl-phenyl), 6.73(s, 1H, Cl-phenyl), 6.53 (s, 2H, pyrimidinyl), 5.44 (s, 2H, NH₂); HPLC(System 1): 5.43 min.

Example 36N-[4-(pyridin-4-yl-oxy)-3-methyl-phenyl]-N′-(3-trifluoromethyl-phenyl)-urea

The title compound is synthesized according to the preparation ofcompound of Example 35 starting from Stage 36.1: M+H=388.2; ¹H-NMR (400MHz, DMSO-d₆): 9.03/8.90 (s/s, 2H, NH), 8.39 (d, 6.5 Hz, 2H,pyrimidinyl), 8.01 (s, 1H, CF₃-phenyl), 7.53 (d, 7.5 Hz, 1H, CF₃-phenyl,7.46 (m, 2H, CH₃-phenyl), 7.35 (d, 8.5 Hz, 1H, CF₃-phenyl), 7.29 (d, 7.5Hz, 1H, CF₃-phenyl), 7.00 (d, 7.5 Hz, 1H, CH₃-phenyl), 6.76 (d, 6.5 Hz,2H, pyrimidinyl), 3.30 (s, 3H, CH₃); HPLC (System 1): 5.26 min.

Stage 36.1

The compound is synthesized according to the preparation of compound ofStage 35.1: slightly brownish solid: M+H=201.1; ¹H-NMR (400 MHz,DMSO-d₆): 8.36 (d, 6.5 Hz, 2H, pyrimidinyl), 6.73 (m, 3H,pyrimidiny/phenyl-CH₃), 6.49 (s, 1H, phenyl-CH₃), 6.44 (m, 2H,phenyl-CH₃), 5.06 (s, 2H, NH₂), 1.96 (s, 3H, CH₃); R_(f)(hexane/AcOEt=1:2): 0.14.

Example 371-(3-Methoxy-5-trifluoromethyl-phenyl)-3-[4-(pyridin-4-yloxy)-phenyl]-urea

The title comound is synthesized analogously to the describedprocedures: M+H=404.1; ¹H-NMR (400 MHz, DMSO-d₆): 9.07 (s, 1H, NH), 8.87(s, 1H, NH), 8.40 (d, Hz, 6.5 Hz, 2H, pyridinyl), 7.55 (d, 9.5 Hz, 2H,oxo-phenyl-amine), 7.48 (s, 1H, CH₃—O—CF₃-phenyl), 7.24 (s, 1H,O—CH₃/CF₃-phenyl), 7.09 (d, 9.5 Hz, 2H, oxo-phenyl-amine), 6.84 (d, 6.5Hz, 2H, pyridinyl), 6.80 (s, 1H, CH₃—O—/CF₃phenyl), 3.79 (s, 3H, CH₃—O);R_(f) (MeOH/CH₂Cl₂=1:3): 0.19; m.p.=162.5-164.5° C.

Example 381-{4-[Bis-(2-methoxy-ethyl)-amino]-3-trifluoromethyl-phenyl]-3-[4-(pyridin-4-yloxy)-phenyl]-urea

The title compound is synthesized according to the preparation ofcompound of Example 1 starting fromN*1*,N*1*-bis-(2-methoxy-ethyl)-2-trifluoromethyl-benzene-1,4diamine(Stage 38.1): M+H=505.0; ¹H-NMR (400 MHz, DMSO-d₆): 8.97 (s, 1H, NH),8.86 (s, 1H, NH), 8.40 (d, 6.5 Hz, 2H, pyridinyl), 7.88 (s, 1H,CF₃—CH₂—O—/CF₃-phenyl), 7.55 (m, 4H, oxo-phenyl-amine,CF₃—CH₂—O—/CF₃-phenyl), 7.11 (d, 9.5 Hz, 2H, oxo-phenyl-amine), 6.84 (d,6.5 Hz, 2H, pyridinyl), 3.27 (t, 8 Hz, 4H, CH₂), 3.16 (s, 6H, CH₃—O),3.08 (t, 8 Hz, 4H, CH₂); R_(f) (acetone/CH₂Cl₂=1:3): 0.20.

Stage 38.1

The compound is synthesized by nucleophilic substitution reaction from1-bromo-4-nitro-2-trifluoromethyl-benzene withbis-(2-methoxy-ethyl)amine (140° C., 4 h) and further hydrogenolyticreduction of the nitro-function to the amine by means of Raney Nickel:M+H=293.0; ¹H-NMR (400 MHz, DMSO-d₆): 7.24 (d, 9 Hz, 1H), 6.77 (m, 2H),5.37 (s/broad, 2H, NH₂), 3.26 (t, 8 Hz, 4H, CH₂), 3.16 (s, 6H, CH₃—O),2.98 (t, 8 Hz, 4H, CH₂); R_(f) (acetone/CH₂Cl₂=1:3): 0.50; m.p.=64.5-65°C.

Example 391-(4-Diethylamino-3-trifluoromethyl-phenyl)-3-[4-yloxy)-phenyl]-urea

The title compound is synthesized according to the preparation ofcompound of Example 1 starting fromN*1*,N*1*-diethyl-2-trifluoromethyl-benzene-1,4diamine (Stage 39.1):M+H=445.0; ¹H-NMR (400 MHz, DMSO-d₆): 8.94 (s, 1H, NH), 8.86 (s, 1H,NH), 8.42 (d/broad, 6.5 Hz, 2H, pyridinyl), 7.89 (s, 1H,NEt₂-/CF₃-phenyl), 7.59 (d/broad, 9.5 Hz, 1H, NEt₂-/CF₃-phenyl), 7.56(d, 9.5 Hz, 2H, oxo-phenyl-amine), 7.43 (d, 9.5 Hz, 1H,NEt₂-/CF₃-phenyl), 7.11 (d, 9.5 Hz, 2H, oxo-phenyl-amine), 6.84 (d, 6.5Hz, 2H, pyridinyl), 2.84 (qu, 7.5 Hz, 4H, CH₂), 0.90 (t, 7.5 Hz, 6H,CH₃); R_(f) (acetone/CH₂Cl₂=1:3): 0.21; m.p.: 60° C. (decomp.).

Stage 39.1

The compound is synthesized according to the preparation of Stage 38.1:M+H=293.0; ¹H-NMR (400 MHz, DMSO-d₆): 7.24 (d, 9 Hz, 1H), 6.77 (m, 2H),5.37 (s/broad, 2H, NH₂), 3.26 (t, 8 Hz, 4H, CH₂), 3.16 (s, 6H, CH₃—O),2.98 (t, 8 Hz, 4H, CH₂); R_(f) (acetone/CH₂Cl₂=1:3): 0.50.

Example 40N-Methyl-C-[4-(6-{4-[3-(3-trifluoromethyl-phenyl)-ureido]-phenoxy}pyrimidin-4-ylamino)-phenyl]-methanesulfonamide

The title compound is synthesized in analogy to the preparation ofcompound of Example 22: M+H=572.8; ¹H-NMR (400 MHz, DMSO-d₆): 9.61 (s,1H, NH), 9.01/8.87 (s/s, 2H, NH-urea), 8.36 (s, 1H, pyrimidinyl), 8.02(s, 1H, CF₃-phenyl), 7.58 (m, 3H, amino-phenyl/CF₃-phenyl), 7.50 (m, 3H,oxo-phenyl-urea/CF₃-phenyl), 7.12 (d, 8.0 Hz, 2H, oxo-pheny-urea), 6.85(q, 5.0 Hz, 1H, NH-SO₂), 6.04 (s, 1H, pyrimidinyl), 4.22 (s, 2H, CH₂),2.57 (d, 5.0 Hz, 3H, CH₃); HPLC (System 1): 5.80 min.

Examples 411-[4-(4-Methyl-piperazin-1-yl)-3-trifluoromethyl-phenyl]-3-[4-(pyridin-4-yloxy)-phenyl]-urea

The title compound is synthesized according to the preparation ofExample 1 starting from4-(4-methyl-piperazin-1-yl)-3-trifluoromethyl-phenylamine (Stage 41.1):M+H=472.0; ¹H-NMR (400 MHz, DMSO-d₆): 9.18 (s, 1H, NH), 9.08 (s, 1H,NH), 8.43 (d, Hz, 6.5 Hz, 2H, pyridinyl), 7.90 (s, 1H, 3-CF₃-phenyl),7.59 (d, 9.5 Hz, 1H, 3-CF₃-phenyl), 7.54 (d, 8.0 Hz, 2H, oxo-phenyl),7.49 (t, 8.0 Hz, 1H, 3-CF₃-phenyl), 7.13 (d, 8.0 Hz, 2H, oxo-phenyl),6.89 (d, 6.5 Hz, 2H, pyridinyl), 2.85 (s/broad, 4H, piperidinyl), 2.56(s/broad, 4H, piperidinyl), 2.32 (s/broad, 3H, NMe); R_(f)(MeOH/CH₂Cl₂=1:9): 0.10; m.p.>100° C. (decomp.).

Stage 41.1

The compound is synthesized according to the preparation of Stage 39.1:M+H=260.1; ¹H-NMR (400 MHz, DMSO-d₆): 7.21 (d, 9 Hz, 1H), 6.74 (m, 2H),5.35 (s/broad, 2H, NH₂), 2,70 (m/broad, 4H, CH₂), 2.36 (s/broad, 4H,CH₂), 2.18 (s, 3H, CH₃); R_(f) (MeOH/CH₂Cl₂=1:5): 0.17; m.p.=121-123° C.

Example 421-[4-(2-Hydroxy-proylamino)-3-trifluoromethyl-phenyl]-3-[4-(pyridin-4-yloxy)-phenyl]-urea

The title compound is synthesized according to the preparation ofExample 22 starting from4-(4-methyl-piperazin-1-yl)-3-trifluoromethyl-phenylamine (Stage 42.1):M+H=447.0; ¹H-NMR (400 MHz, DMSO-d₆): 8.70 (s, 1H, NH), 8.48 (s, 1H,NH), 8.39 (d/broad, 6.5 Hz, 2H, pyridinyl), 7.62 (s, 1H,HO-propyl-NH-/CF₂phenyl), 7.53 (d, 11 Hz, 2H, oxo-phenyl-amine), 7.37(d/broad, 9.5 Hz, 1H, HO-propyl-NH-/CF₃-phenyl), 7.09 (d, 11 Hz, 2H,oxo-phenyl-amine), 6.84 (d, 6.5 Hz, 2H, pyridinyl), 6.78 (d, 9.5 Hz, 1H,HO-propyl-NH—/CF₃-phenyl), 4.90 (t/broad, 1H, NH), 4.84 (d, 6.5 Hz, 1H,OH), 3.81 (sept/broad, 1H, CH), 3.11/2.90 (m/m, 2H, CH₂), 1.10 (d, 6.5Hz, 3H, CH₃); R_(f) (acetone/CH₂Cl₂=1:3): 0.11; m.p.: 140

Stage 42.1

The compound is synthesized according to the preparation of Stage 39.1:M+H =236.2; ¹H-NMR (400 MHz, DMSO-d₆): 6.74 (s, 1H) 6.72 (d, 9 Hz, 1H),6.60 (d, 9.0 Hz, 1H), 4.80 (s/broad, 1H, NH), 4.67 (2, 2H.NH₂), 4.37(m/broad, 1H, OH), 3.80 (m/broad, 1H, CH), 3.02 (m/broad, 1H, CH₂), 2.79(m/broad, 1H, CH₂), 1.07 (s, 3H, CH₃); R_(f) (hexane/AcOEt=1:1): 0.13;m.p.=91-93° C.

Example 431-(4-Methyl-3-trifluoromethyl-phenyl)-3-[4-(pyridin-4-yloxy)-phenyl]-urea

The comound is synthesized analogously to the described procedures:M+H=388.2; ¹H-NMR (400 MHz, DMSO-d₆): 8.96 (s, 1H, NH), 8.84 (s, 1H,NH), 8.42 (d/broad, 6.5 Hz, 2H, pyridinyl), 7.93 (s, 1H, CF₃/Me-phenyl),7.56 (d, 9.5 Hz, 2H, oxo-phenyl-amine), 7.52 (d, 9.0 Hz, 1H,CF₃/Me-phenyl), 7.33 (d, 9.0 Hz, 1H, CF₃/Me-phenyl), 7.10 (d, 9.5 Hz,2H, oxo-phenyl-amine), 6.84 (d, 6.5 Hz, 2H, pyridinyl), 2.36 (s, 3H,CH₃); R_(f) (acetone/CH₂Cl₂=1:3): 0.25; m.p.: 149° C. (decomp.).

Example 44 5-(pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylic acid[4-(2,2,2,-trifluoro-ethoxy)-3-trifluoromethyl-phenyl]-amide

Is prepared in analogy to the synthesis of compound of Example 20:M+H=497.9; ¹H-NMR (400 MHz, DMSO-d₆): 8.73 (s, 1H, NH), 8.40 (d, Hz, 6.5Hz, 2H, pyridinyl), 7.92 (m, 2H, indolinyl/3-CF₃-phenyl), 7.82 (d, 8.0Hz, H, 3-CF₃-phenyl), 7.36 (t, 8.0 Hz, 1H, 3-CF₃-phenyl), 7.04 (s, 1H,indoline), 6.95 (dd, 9.5 Hz, 3.5 Hz, 1H, indoline), 6.84 (d, 6.5 Hz, 2H,pyridinyl), 4.89 (q, 9.0 Hz, 2H, CF₃—CH₂), 4.26 (t, 7.5 Hz, 2H,CH₂-indolinyl), 3.17 (t, 7.5 Hz, 2H, CH₂-indolinyl); R_(f)(acetone/CH₂Cl₂=1:3): 0.20.

Example 451-{4-[6-(4-Hydroxy-phenylamino)-pyrimidin-4-yloxy]-phenyl}-3-(4-morpholin-4-yl-3-trifluoromethyl-phenyl)-urea

The title compound is synthesized according to the synthesis of compoundof Example 22: M+H=564.8; ¹H-NMR (400 MHz, DMSO-d₆): 9.23 (s, 2H, NH,OH), 8.96/8.78 (s/s, 2H, 3 NH-urea), 8.21 (s, 1H, pyrimidinyl), 7.92 (s,1H, morpholinyl-phenyl), 7.53 (m, 3H,morpholinyl-phenyl/oxo-phenyl-amino), 7.24 (d, 8.5 Hz, 1H,morpholinyl-phenyl), 7.08 (d, 9.0 Hz, 2H, oxo-phenyl-urea), 6.69 (d, 9.0Hz, 2H, oxo-phenyl-amino), 5.87 (s, 1H, pyrimidinyl), 3.65 (m, 4H, CH₂),2.79 (m, 4H, CH₂); R_(f) (NH₃/MeOH/CH₂Cl₂=0.01:1:9): 0.33.

Example 46C-[4-(6-{4-[3-(4-Ethyl-phenyl)-ureido]-phenoxy}-pyrimidin-4-ylamino)-phenyl]-N-methyl-methanesulfonamide

1-Ethyl-4-isocyanato-benzene (25.7 mg, 0.175 mmol) is slowly added toC-{4-[6-(4-amino-phenoxy)-pyrimidin-4-ylamino]-phenyl}-N-methyl-methanesulfonamide(45 mg, 0.117 mmol) and pyridine (18.9 mL, 0.234 mmol) dissolved inTHF/DMF (2:1, 3 mL) at 0° C. After stirring at rt for 4 h, the solventis evaporated under reduced pressure, and the product is isolated bypreparative thin layer chromatography (4 plates of 20×20 cm,acetone/CH₂Cl₂=3.7) giving the compound of Example 46 as a white solid:M+H=532.5; ¹H-NMR (400 MHz, DMSO-d₆): 8.70/8.57(s/s, 2H, NH-urea), 8.33(s, 1H, pyrimidinyl), 7.59 (d, 9.5 Hz, 2H, phenyl-CH₂), 7.55 (d, 9.5 Hz,2H, amino-phenyl), 7.36 (d, 9.5 Hz, 2H, ethyl-phenyl), 7.25 (d, 9.5 Hz,2H, pheny-CH₂), 7.10 (d, 9.5 Hz, 4H, ethyl-phenyl/amino-phenyl), 6.83(m, 2H, NH-sulfonamide), 6.05 (s, 1H, pyrimidinyl), 4.22 (s, 2H, CH₂),2.57 (m, 5H, CH₃-ethyl/NH—CH₃), 1.16 (t, 7.5 Hz, 3H, CH₃-ethyl); R_(f)(acetone/CH₂Cl₂=3:7): 0.32.

Example 471-(4-[6-(4-Methoxy-phenylamino)-pyrimidin-4-yloxy]-phenyl}-3-(4-morpholin-4-yl-3-trifluoromethyl-phenyl)-urea

[6-(4-Amino-phenoxy)-pyrimidin-4-yl]-(4methoxy-phenyl)-amine (Stage47.1; 200 mg, 0.648 mmol) and triethylamine (0.075 ml, 0.54 mmol)dissolved in CH₂Cl₂ (6 mL) is slowly added to a solution of triphosgene(64 mg, 0.213 mmol) in CH₂Cl₂ (10 mL) at 4° C. After stirring at rt for15 min, a solution of 4-morpholin-4-yl-3-trifluoromethyl-phenylamine(160 mg, 0.648 mmol) and triethylamine (0.075 ml, 0.54 mmol) in CH₂Cl₂(6 mL) is added and the reaction mixture is stirred for 2 h. Afteradding concentrated NaHCO₃ solution (20 mL), the product is extractedwith CH₂Cl₂ (20 ml, 2×). The combined organic phases are washed withwater (20 mL), dried (Na₂SO₄), and concentrated under reduced pressure.The product is purified by flash chromatography (silica gel, 2.5×20 cm,MeOH/CH₂Cl₂=5:95) giving a white solid: M+H=580.9; ¹H-NMR (400 MHz,DMSO-d₆): 9.32 (s, 1H, NH), 9.35/8.78 (s/s, 2H, NH-urea), 8.23 (s, 1H,pyrimidine), 7.89 (s, phenyl-CF₃), 7.58 (d, 8.5 Hz, 1H, phenyl-CF₃),7.53 (d, 8.5 Hz, 1H, phenyl-CF₃), 7.49/7.40/7.08/6.86 (d/d/d/d, 9.0 Hz,8H, phenyl-oxo/phenyl-OMe), 5.91 (s, 1H, pyrimidinyl), 3.70 (s, 3H,CH₃—O), 3.66/2.79 (m/m, 4H/4H, morpholinyl); R_(f) (MeOH/CH₂Cl₂=5:95):0.16; HPLC (System 1): 6.31 min.

Stage 47.1:[6-(4-Amino-phenoxy)-pyrimidin-4-yl]-(4-methoxy-phenyl)-amine

(4-Methoxy-phenyl)-[6-(4-nitro-phenoxy)-pyrimidin-4-yl]-amine (Stage47.2; 1.06 g, 3.13 mmol) dissolved in THF/EtOH (1:2; 27 mL) ishydrogenated in the presence of Raney-Ni (0.2 g) during 36 h. Afterfiltering off the catalyst and washing with EtOH (20 mL), the solvent isevaporated under reduced pressure and flash chromatographed (silica gel,4.5×26 cm, MeOH/CH₂Cl₂=5:95) giving a white solid: M+H=309.1; ¹H-NMR(400 MHz, DMSO-d₆): 9.23 (s, 1H, NH-pyrimidinyl), 8.22 (s, 1H,pyrimidine), 7.40/6.85/6.79/6.57 (d/d/d/d, 9.0 Hz, 8H,phenyl-oxo/phenyl-OMe), 5.81 (s, 1H, pyrimidinyl), 5.07 (s, 2H, NH₂),3.72 (s, 3H, CH₃—O); R_(f) (MeOH/CH₂Cl₂=1:9): 0.44; HPLC (System 1):3.45 min.

Stage 47.2:(4-Methoxy-phenyl)-[6-(4-nitro-phenoxy)-pyrimidin-4-yl]-amine

4-Chloro-6-(4-nitro-phenoxy)-pyrimidine (1 g, 3.97 mmol), p-anisidine(514 mg, 4.178 mmol), and diisopropylethylamine (0.715 mL, 4.178 mmol)dissolved in 2-propanol (27 mL) are stirred under reflux under Ar. After16 h, p-anisidine (245 mg, 1.99 mmol) is added and the reaction mixtureis stirred for additional 20 h. After cooling the reaction mixture downto rt, compound of Stage 47.2 precipitates as white crystals: M+H=339.1;¹H-NMR (400 MHz, DMSO-d₆): 9.49 (s, 1H, NH-pyrimidinyl), 8.25 (s, 1H,pyrimidine), 8.23/7.40/6.90 (d/d/d/, 9.0 Hz, 2H/4H/2H,phenyl-oxolphenyl-OMe), 6.18 (s, 1H, pyrimidinyl), 3.72 (s, 3H, CH₃—O);R_(f) (MeOH/CH₂Cl₂=1:9): 0.44; HPLC (System 1): 6.15 min.

Example 48N-Methyl-C-[4-(6-{4-[3-(4-morpholin-4-yl-3-trifluoromethyl-phenyl)-ureido]-phenoxy}-pyrimidin-4-ylamino)-phenyl]-methanesulfonamide

4-Morpholin-4-yl-3-trifluoromethyl-phenylamine (28.8 mg, 0.117 mmol),triethylamine (0.05 mL, 0.36 mmol), and triphosgene (35 mg, 0.117 mmol)are dissolved in CHCl₃ (2 mL) at 0° C. After stirring at rt for 15 min,C-{4-[6-(4-amino-phenoxy)-pyrimidin-4-ylamino]-phenyl}-N-methyl-methanesulfonamide(45 mg, 0.117 mmol) and triethylamine (0.05 mL) dissolved in DMF/DMSO(4:1; 5 mL) are added and strirring is continued for 16 h. Afterevaporating the solvent under reduced pressure, the product is isolatedby preparative thin layer chromatography (four 20×20 cm plates,acetone/CH₂Cl₂=3.7) giving the compound of Example 48 as a white solid:M+H=658.1; ¹H-NMR (400 MHz, DMSO-d₆): 9.57 (s, 1H, phenyl-NH-phenyl),8.97/8.81(s/s, 2H, NH-urea), 8.34 (s, 1H, pyrimidinyl), 7.89 (s, 1H,phenyl-CF₃), 7.58 (d, 9.0 Hz, 3H, phenyl-CF₃/phenyl-CH₂), 7.50 (d, 9.0Hz, 3H, phenyl-CF₃/oxo-phenyl), 7.24 (d, 9.0 Hz, 2H, phenyl-CH₂), (d,9.0 Hz, 2H, oxo-phenyl), 6.83 (d, 4.0 Hz, 1H, NH-sulfonamide), 6.06 (s,1H, pyrimidinyl), 4.23 (s, 2H, CH₂), 3.64/2.78 (m/m, 4H/4H,morpholinyl), 2.52 (d, 4.0 Hz, CH₃—N); R_(f) (acetone/CH₂Cl₂=3:7): 0.40.

Example 491-{4-[6-(3-Hydroxy-phenylamino)-pyrimidin-4-yloxy]-phenyl}-3-(4-morpholinyl-4-yl-3-trifluoromethyl-phenyl)-urea

To a solution of1-(4-{6-[3-(tert-butyl-dimethyl-silanyloxy)phenylamino]-pyrimidin-4-yloxy}-phenyl)-3-(4-morpholin-4-yl-3-trifluoromethyl-phenyl)-urea(Stage 49.1) (283 mg, 0.415 mmol) in MeCN/THF (1.9 mL/0.95 mL), HF (30%in pyridine; 0.5 mL) is added at 4° C. After stirring at rt for 2 h,phosphate buffer (pH=7, 10 mL) is added and the product is extractedwith AcOEt (2×, 20 mL). The combined organic layers are washed with H₂O(20 mL), dried (MgSO₄), concentrated under reduced pressure, and flashchromatographed (silica gel, 3.0×20 cm, MeOH/CH₂Cl₂=5:95) giving a whitesolid: M+H=566.9; ¹H-NMR (400 MHz, DMSO-d₆): 9.40/9.35 (s/s, 2H,NH-urea), 9.05/8.87 (s/s, 2H, OH/NH), 8.33 (s, 1H, pyridinyl), 7.92 (s,1H, phenyl-CF₃), 7.62 (d, 8.5 Hz, 1H, phenyl-OH), 7.52 (d, 9.0 Hz, 3H,phenyl-oxo/phenyl-CF₃), 7.15 (s, 1H, phenyl-OH), 7.13 (d, 9.0 Hz, 2H,phenyl-oxo), 7.06 (t, 9.0 Hz, 1H, phenyl-OH), 6.97 (d, 9.0 Hz, 1H,phenyl-OH), 6.41 (d, 8.5 Hz, 1H, phenyl-CF₃), 6.06 (s, 1H, pyrimidinyl),3.69/2.81 (m/m, 4H/4H, morpholinyl); R_(f)(MeOH/CH₂Cl₂=1:9): 0.31; HPLC(System 1): 5.80 min.

Stage 49.1:1-(4-{6-[3-(tert-Butyl-dimethyl-silanyloxy)-phenylamino]-pyrimidin-4-yloxy}-phenyl)-3-(4-morpholin-4-yl-3-trifluoromethyl-phenyl)-urea

[6-(4-Amino-phenoxy)-pyrimidin-4-yl]-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-amine(Stage 49.2; 121 mg, 0.489 mmol) and triethylamine (0.057 mL, 0.83 mmol)dissolved in CH₂Cl₂ (6 mL) are added to a solution of triphosgene (48mg, 0.161 mmol) in CH₂Cl₂ (10 mL) at 4° C. under Ar. After stirring atrt for 15 min, 4-morpholin-4-yl-3-trifluoromethyl-phenylamine (121 mg,0.489 mmol) and triethylamine (0.057 mL) dissolved in CH₂Cl₂ (6 mL) areadded and the reaction mixture is stirred for 2 h at rt. After addingconcentrated NaHCO₃ (20 mL), the reaction mixture is extracted withCH₂Cl₂ (20 ml, 2×). The combined organic layers are washed with H₂O,dried (Na₂SO₄), concentrated under reduced pressure, and flashchromatograped (silica gel, 2.5×22 cm, MeOH/CH₂Cl₂=2:098) to give thecompound of Stage 49.1 as a white solid: M+H=680.9; ¹H-NMR (400 MHz,DMSO-d₆): 9.49 (s, 1H, NH-pyrimidinyl), 8.94/8.80 (s/s, 2H, NH-urea),8.33 (s, 1H, pyrimidinyl), 7.89 (s, 1H, phenyl-CF₃), 7.59 (d, 8.5 Hz,1H, phenyl-CF₃), 7.50 (d, 9.0 Hz, 3H, phenyl-OTBS/phenyl-oxo), 7.23(s/broad, 1H, phenyl-OTBS), 7.16 (t, 8.0 Hz, 1H, phenyl-OTBS), 7.11 (d,9.0 Hz, 3H, phenyl-OTBS/pheny/-oxo), 6.44 (d/broad, 8.0 Hz, 1H,phenyl-CF₃), 6.02 (s, 1H, pyrimidinyl), 3.69/2.80 (m/m, 4H/4H,morpholinyl) 0.92 (s, 9H, tert-butyl-Si), 0.20 (s, 6H, Me-Si); R_(f)(MeOH/CH₂Cl₂=5:95): 0.31; HPLC (System 1): 8.54 min.

Stage 49.2:[6-(4-Amino-phenoxy)-pyrimidin-4-yl]-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-amine

[3-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-[6-(4-nitro-phenoxy)-pyrimidin-4-yl]-amine(Stage 49.3, 1.01 g, 2.306 mmol) dissolved in EtOH/THF (2:1; 26 mL) arehydrogenated in the presence of Raney-Ni (0.2 g) for 22 h. Afterfiltering off the catalyst and washing with EtOH (20 mL), the reactionsolution is evaporated and the crude product is flash chromatographed(silica gel, 4.5×28 cm, MeOH/CH₂Cl₂=2:98) to give compound of Stage 49.2as a white solid: M+H=409.1; ¹H-NMR (400 MHz, DMSO-d₆): 9.39 (s, 1H,NH-pyrimidinyl), 8.35 (s, 1H, pyrimidinyl), 7.23 (s, 1H, phenyl-OTBS),7.17 (d, 8.5 Hz, 1H, phenyl-OTBS), 7.11 (t, 8.5 Hz, 1H, phenyl-OTBS),7.16 (t, 8.0 Hz, 1H, phenyl-OTBS), 7.11 (d, 9.0 Hz, 1H, phenyl-OTBS),6.82/6.58 (d/d, 8.5 Hz/8.5 Hz, 4H, phenyl-oxo), 6.44 (d, 8.5 Hz, 1H,phenyl-OTBS), 5.92 (s, 1H, pyrimidinyl), 5.09 (s, 2H, NH₂), 0.96 (s, 9H,tert-butyl-Si), 0.19 (s, 6H, Me-Si); R_(f) (MeOH/CH₂Cl₂=5:95): 0.32;HPLC (System 1): 6.31 min.

Stage 49.3:[3-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-[6-(4-nitro-phenoxy)-pyrimidin-4-yl]-amine

3-[6-(4-Nitro-phenoxy)-pyrimidin-4-ylamino]-phenol (Stage 49.4; 830 mg,2.56 mmol), tert-butyl-dichlorosilane (579 mg, 3.84 mmol), andtriethylamine (0.536 mL, 3.84 mmol) dissolved in DMF (11 mL) are stirredunder Ar for 3 at rt. After adding H₂O (20 mL), the reaction mixture isextracted with CH₂Cl₂ (20 mL, 2×). The combined organic phases arewashed with H₂O (10 mL), dried (Na₂SO₄), concentrated under reducedpressure, and flash chromatographed (silica gel, 5.5×30 cm,MeOH/CH₂Cl₂=5:95) to give the compound of Stage 49.3 as a white solid:M+H=439.0; ¹H-NMR (400 MHz, DMSO-d₆): 9.65 (s, 1H, NH-pyrimidinyl), 8.35(s, 1H, pyrimidinyl), 7.23 (s, 1H, phenyl-OTBS), 7.17 (m, 2H,phenyl-OTBS), 6.50 (d, 8.0 Hz, 1H, phenyl-OTBS), 8.29/7.43 (d/d, 8.5Hz/8.5 Hz, 4H, phenyl-oxo), 6.28 (s, 1H, pyrimidinyl), 0.96 (s, 9H,tert-butyl-Si), 0.19 (s, 6H, Me-Si); R_(f) (MeOH/CH₂Cl₂=5:95): 0.34;HPLC (System 1): 8.87 min.

Stage 49.4: 3-[6-(4-Nitro-phenoxy)-pyrimidin-4-ylamino]-phenol

4-Chloro-6-(4-nitro-phenoxy)-pyrimidine (1 g, 3.97 mmol), 3-amino-phenol(456 mg, 4.175 mmol), diisopropylethylamine (0.715 mL, 4.175 mmol)dissolved in 2-propanol (17 mL) are stirred under reflux. After 16 and22 h, the same amount of 3-amino-phenol and diisopropylethylamine isadded to the reaction mixture. After 42 h, the solvent is evaporatedunder reduced pressure, and the reaction mixture is flashchromatographed (silica gel, 4.5×26 cm, MeOH/CH₂Cl₂=5:95) to give thecompound of Stage 49.4 as a white solid: M+H=325.1; ¹H-NMR (400 MHz,DMSO-d₆): 9.59/9.37 (s/s, 2H, NH-pyrimidinyl/OH), 8.35 (s, 1H,pyrimidinyl), 8.27/7.43 (d/d, 9.5 Hz/9.5 Hz, 2H/2H, phenyl-NO₂), 7.12(s, 1H, phenyl-OH), 7.06 (t, 8.5 Hz, 1H, phenyl-OH), 6.94/6.44 (d/d, 8.5Hz/8.5 Hz, 2H, phenyl-OH), 6.31 (s, 1H, pyrimidinyl); R_(f)(MeOH/CH₂Cl₂=1:9): 0.58; HPLC (System 1): 5.43 min.

The following compounds are synthesized according to the procedure ofthe synthesis of compound of Example 1 (Table 5). TABLE 5 Ex. StructureAnalytical data 50

M + H = 417.0; R_(f) (AcOEt/hexane = 2:1): 0.21; Anal.: C: 57.11(57.70)%, H: 3.61 (3.63)%, N: 13.43 (13.46)%. 51

M + H = 464.0; R_(f) (AcOEt/hexane = 2:1): 0.13; Anal.: C: 66.50(67.38)%, H: 4.59 (4.35)%, N: 8.64 (9.07)%. 52

M + H = 472.0; R_(f) (CH₂Cl₂/MeOH = 4:1): 0.41. 53

M + H = 479.0; R_(f) (CH₂Cl₂/MeOH = 95:5): 0.12; HPLC (System 1): 5.01min. 54

M + H = 388.0; R_(f) (CH₂Cl₂/acetone = 3:1): 0.24; HPLC (System 1): 4.97min; Anal.: C: 60.58 (62.01)%, H: 4.32 (4.16)%, N: 10.14 (10.85)%.

The starting material 4-(pyridin-4-ylmethoxy)-phenylamine (Stage 51.1)for the synthesis of the compounds of Example 51 and 54 is generatedfrom 4-(4-nitro-phenoxymethyl)-pyridine by hydrogenation in the presenceof Raney-Ni in EtOH at 40° C. during 3 h: M+H=201.0; R_(f)(CH₂Cl₂/acetone=85:15): 0.17.

4-(4-Nitro-phenoxymethyl)pyridine

4-hydroxymethyl-pyridine (2.23 g, 20 mmol) is added to a suspension ofKOH (1.32 g, 20 mmol) and Aliquat 336 (0.937 mL). After stirring for 5min at rt, 1-chloro-4-nitro-benzene (2.68 g, 16.7 mmol) is added. Theresulting reaction mixture is further stirred at rt for 5 min and thenat 80° C. for 2 h. The reaction mixture is filtered over silica gel (15g), concentrated under reduced pressure, and flash chronatographed(silica gel, 3×50 cm, acetone/CH₂Cl₂=5:95→15:85) to give the titlecompound as a yellow solid: M+H=231.0; ¹H-NMR (400 MHz, DMSO-d₆): 8.58(d, 6.5 Hz, 2H, pyrimidinyl), 8.22 (d, 8.5 Hz, 2H, phenyl-NO₂), 7.44 (d,6.5 Hz, pyrimidinyl), 7.21 (d, 8.5 Hz, 2H, phenyl-NO₂), 5.34 (s, 2H,CH₂); R_(f) (acetone/CH₂Cl₂=15:85): 0.32; HPLC (System 1): 3.40 min.

The substituted 3-trifluoromethyl-anilines for the synthesis ofcompounds of Examples 52 and 53 are prepared from the1-bromo-3-nitro-5-trifluoromethyl-benzene by nucleophilic substitutionof the bromine by the corresponding amine and subsequent hydrogenationof the nitro function to the amine by means of Raney-Ni.

Example 55 1-(4-Aminomethyl-phenyl)-3-[4-(pyridin-4-yloxy)-phenyl]-urea

4-{3-[4-(Pyridin-4-yloxy)-phenyl]-ureido}-benzyl)-carbamic acid benzylester (Stage 55.1) (0.1 g, 0.213 mmol) dissolved in EtOH/THF (2:1, 6 mL)is hydrogenated in the presence of Pd/C (Engelhard 4505, 100 mg) for 5h. After filtering of the catalyst, the reaction solution isconcentrated under reduced pressure and flash chromatographed (silicagel, 2.5×46 cm, CH₂Cl₂/MeOH/conc. NH₃=9:1:0.01→85:15:0.1) to give thecompound of Example 55 as a white solid: M+H=335.0; R_(f)(CH₂Cl₂/MeOH/conc. NH₃=85:15:0.1): 0.15; HPLC (System 1): 5.74 min.

Stage 55.1: 4-{3-[4-(Pyridin-4-yloxy)-phenyl]-ureido}-benzyl)-carbamicacid benzyl ester

The compound is synthesized in analogy to the preparation of compound ofExample 1 starting from (4-amino-benzyl)-carbamic acid benzyl ester(Stage 55.2): M+H=469.1; R_(f) (CH₂Cl₂/MeOH=85:15): 0.26; HPLC (System1): 4.85 min.

Stage 55.2: (4-amino-benzyl)-carbamic acid benzyl ester

After stirring [4-(benzyloxycarbonylamino-methyl)phenyl]-carbamic acidtert-butyl ester (Stage 55.3) (1.06 g, 2.97 mmol) in TFA/H₂O (95:5, 10mL), the solvent is evaporated in vacuo. The residue is taken up inNaHCO₃ (20 mL) and extracted with AcOEt (20 mL). The organic phase isdried (MgSO₄), concentrated under reduced pressure, and flashchromatographed (silica gel, 4.5×52 cm, MeOH/CH₂Cl₂=5:95) to give thecompound of Stage 55.2 as a colorless solid: M+H=257.1; R_(f)(CH₂Cl₂/MeOH=95:5): 0.67; HPLC (System 1): 3.62 min.

Stage 55.3: [4-(benzyloxycarbonylamino-methyl)-phenyl]-carbamic acidtert-butyl ester

To a solution of 4-(aminomethyl)-1-N-Boc-aniline (1 g, 4.5 mmol)dissolved in CH₂Cl₂ (10 mL), triethylamine (0.626 mL, 4.5 mmol) andchloro-formic acid benzyl ester (0.698 mL, 4.95 mmol) are added, thereaction solution is stirred at rt for 2 h, taken up in CH₂Cl₂ (10 mL)and washed with concentrated NaHCO₃ solution (20 mL) and H₂O (20 mL).The aqueous phase is washed with CH₂Cl₂ (20 mL). The combined organicphases are dried (Na₂SO₄), concentrated under reduced pressure and flashchromatographed (silica gel, 3.5×60 cm, AcOt/hexane=1:4) to give thecompound of Stage 55.3 as a white solid: M+H=355.1; R_(f)(AcOEt/hexane=1:4): 0.15; HPLC (System 1): 6.53 min.

Example 561-[4-(6-Chloro-pyrimidin-4-yloxy)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea

After stirring 3-trifluoromethyl-phenyl isocyanate (412 mg , 2.2 mmol),4-(6-chloro-pyrimidin-4-yloxy)anillne (Stage 56.1; 0.25 g, 1.1 mmol),and pyridine (0.18 mL) over night, the reaction solution is concentratedunder reduced pressure and flash chromatographed (silica gel, 2.5×17 cm;acetone/CH₂Cl₂=5:95→1:9) to give the compound of Example 56 as a whitesolid material: M+H=408.9/410.9; ¹H-NMR (400 MHz, DMSO-d₆): 9.07 (s, 1H,NH), 8.89 (s, 1H, NH), 8.63 (d, 2.0 Hz, 1H, pyridinyl), 8.01 (s, 1H,3-CF₃-phenyl), 7.57 (d/broad, 8.0 Hz, 1H, CF₃-pheny), 7.52 (d, 9.5 Hz,2H, oxo-phenyl-amine), 7.50 (m, 1H, 3-CF₃-phenyl), 7.32 (d, 2.0 Hz, 1H,pyridinyl), 7.29 (d/broad, 8.0 Hz, 1H, —CF₃-phenyl), 7.15 (d, 9.5 Hz,2H, oxo-phenyl-amine), (d, 6.5 Hz, 2H, pyridinyl); R_(f)(acetone/CH₂Cl₂=1:9): 0.54; m.p.=187.4-189.7° C.

Stage 56.1: 4-(6-chloro-pyrimidin-4-yloxy)-aniline

4-Chloro-6-(4-nitro-phenoxy)-pyrimidine (Stage 56.2; 3.6 g, 14.3 mmol)dissolved in MeOH (250 mL) is hydrogenated in the presence of Raney-Ni(3 g) at 40° C. for 3 d. The reaction solution is filtred, concentratedunder reduced pressure and crystalized from AcOEt/hexane to give thecompound of Stage 56.1: M+H=222/224; ¹H-NMR (400 MHz, DMSO-d₆): 8.62 (s,1H, piperidinyl), 7.13 (s, 1H, piperidinyl), 6.83 (d, 9 Hz, 2H, phenyl),6.56 (d, 9 Hz, 2H, phenyl), 5.12 (s, 2H, NH₂); m.p.=135.5-138.1° C.

Stage 56.2: 4-Chloro-6-(4-nitro-phenoxy)-pyrimidine

4-Nitrophenol (2.8 g, 20.1 mmol), 2,4-dichloro-pyrimidine (3 g, 20.1mmol), NaOH (0.8 g, 20.1 mmol) dissolved in H₂O/acetone (80 mL; 1:1) arestirred at 60-65° C. for 1 h. The reaction solution is concentratedunder reduced pressure and flash chromatographed (silica gel, 4.5×22 cm,AcOEt/hexane=1:4) to give the compound of Stage 56.2 as a white solidmaterial: M+H=252/254; ¹H-NMR (400 MHz, DMSO-d₆): 8.67 (s, 1H,piperidinyl), 8.34 (d, 9 Hz, 2H, phenyl), 7.58 (d, 9 Hz, 2H, phenyl),7.53 (s, 1H, piperidinyl); R_(f) (AcOEt/hexane=1:1): 0.16;m.p.=125.4-126.6° C.

Example 571-[4-(6-Methylamino-pyrimidin-4-yloxy)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea

1-[4-(6-Chloro-pyrimidin-4-yloxy)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea(Example 56) (42.7 mg, 0.1 mmol) is dissolved in methylamine (30% inEtOH, 1 mL) in a sealable tube and heated under Ar for 10 min at 50° C.After evaporating the solvent, the product is purified by preparativeTLC (2 20×20 cm plates, acetone/CH₂Cl₂=3:7) to give the title compoundas a white solid: M+H=404.1; ¹H-NMR (400 MHz, CDCl₃): 8.22 (s, 1H,pyridinyl), 7.84 (s/broad, 1H, NH), 7.62 (s, 1H, 3-CF₃-phenyl), 7.52 (d,8.0 Hz, 1H, CF₃-phenyl), 7.35 (t, 8.0 Hz, 1H, 3-CF₃-phenyl), 7.28 (m,3H, CF₃-phenyl/oxo-phenyl-amine), 6.97 (d, 9.5 Hz, 2H,oxo-phenyl-amine), 5.62 (d/broad, 2H, pyridinyl), 5.44 (s/broad, 1H,NH), 2.89 (s/broad, CH₃—N); R_(f) (acetone/CH₂Cl₂=3:7): 0.36.

The following compounds are synthesized in analogy to the preparation ofcompound of Example 56 by stirring the corresponding chloride and theamine at a temperature range between 20 and 80° C. for a time periodbetween 10 min up to several hours. Structures and analytical data ofthe compounds are given in Table 6. TABLE 6 Ex. Structure Analyticaldata 58

M + H = 489.1; R_(f)CH₂Cl₂/acetone = 7:3): 0.12; ¹H-NMR (400 MHz,CDCl₃): 8.21 (5, 1h, pyrimidinyl), 7.71 (s/broad, 1H, urea), 7.53 (d,8.0 Hz, 1H, aryl), 7.51 (s, 1H, aryl), 7.42 (s/broad, 1H, urea), 7.25(m, 3H, aryl), 6.98 (d, 9.0 Hz, 2H, amino-phenyl- oxy), 5.67 (s, 1H,pyrimidinyl), 5.36 (m/broad, 1H, NH—Me), 3.78 (m, 4H, morpholinyl), 2.91# (d/broad, 3H, NH-Me), 2.84 (m, 4h, morpholinyl). 59

M + H = 364.0; R_(f)(CH₂Cl₂/MeOH = 95:5): 0.16; HPLC (System 1): 5.06min. 60

M + H = 392.0; R_(f)(CH₂Cl₂/MeOH = 95:5): 0.21; HPLC (System 1): 5.52min. 61

M + H = 378.0; R_(f)(CH₂Cl₂/MeOH = 95:5): 0.16; HPLC (System 1): 5.26min; ¹H-NMR (400 MHz, DMSO-d₆): 8.69/8.34 (s/s, 2H, urea), 8.10(s/broad, 1H, pyrimidinyl), 7.44/7.33,/7.09/7.03 (d/d/d/d, 8.5 Hz, 8 H,aryl), 7.00 (s/broad, 1H, NH), 5.65 (s/broad, 1H, pyrimidinyl), 3.25(s/broad, 2H, CH₂), 2.54 (qu, 8.0 Hz, 2H, CH₂), 1.16/1.09 (t/t, # 8.0Hz, CH₃). 62

M + H = 378.0; R_(f)(CH₂Cl₂/MeOH = 95:5): 0.29; HPLC (System 1): 5.33min. 63

M + H = 378.0; R_(f)(hexane/AcOEt = 2:3): 0.40; HPLC (System 1): 4.94min. 64

M + H = 377.1; R_(f)(hexane/AcOEt = 1:4): 0.14; HPLC (System 1): 5.17min. 65

M + H = 391.1; R_(f)(hexane/AcOEt = 2:3): 0.17; HPLC (System 1): 5.49min. 66

M + H = 377.1; R_(f)(hexane/AcOEt = 2:3): 0.20; HPLC (System 1): 5.22min. 67

R_(f) (CH₂Cl₂/acetone = 7:3): 0.19; m.p. = 202-203° C. (decomp.). 68

M + H = 518.9; R_(f)(CH₂Cl₂/MeOH/NH₃ conc. =9:1:0.01): 0.31; HPLC(System 1): 5.32 min. 69

M + H = 490.1; R_(f)(CH₂Cl₂/MeOH/NH₃ conc. =9:1:0.01): 0.17; HPLC(System 1): 4.24 min. 70

M + H = 477.0; R_(f)(CH₂Cl₂/MeOH/NH₃ conc. =9:1:0.01): 0.46; HPLC(System 1): 4.69 min. 71

M + H = 470.0; R_(f)(CH₂Cl₂/MeOH/NH₃ conc. =95:5:0.1): 0.38; HPLC(System 1): 6.04 min. 72

M + H = 364.1; R_(f)(hexane/AcOEt = 1:1): 0.12; HPLC (System 1): 5.18min; ¹H-NMR (400 MHz, DMSO- d₆): 8.66/8.54 (s/s, 2H, urea), 8.12(s/broad, 1H, pyrimidinyl), 7.47/7.33,/7.09/7.09 (d/d/d/d, 8.5 Hz, 8 H,aryl), 7.03 (s/broad, 1H, NH), 6.08 (s/broad, 1H, pyrimidinyl), 2.70(s/broad, 3H, Me-NH), 2.55 (qu, 8.0 Hz, 2H CH₂), 1.13 (t, 8.0 Hz, CH₃).73

M + H = 487.0; R_(f)(AcOEt/hexane = 2:1): 0.45; HPLC (System 1): 6.44min

4-Piperidin-1-yl-3-trifluoromethyl-phenylamine (Stage 73.1) for thesynthesis of compound of Example 74 is synthesized according to thepreparation of compound of Stage 38.1: M+H=245.1; R_(f)(AcOEt/hexane=1:5): 0.11.

Example 741-{4-[2-(4-Hydroxy-phenylamino)-pyrimidin-4-yloxy]-phenyl}-3-(4-morpholin-4yl-3-trifluoromethyl-phenyl)-urea

The compound is synthesized in analogy to the preparation of compound ofExample 22: M+H=566.8; R_(f) (CH₂Cl₂/MeOH): 0.21, HPLC (System 1): 5.59min.

Example 751-{4-[2-(4-Methoxy-phenylamino)-pyrimidin-4-yloxy]-phenyl}-3-(4-piperidin-1yl-3-trifluoromethyl-phenyl)-urea

The compound is synthesized in analogy to the preparation of compound ofExample 22: M+H=578.9; R_(f) (Hexane/AcOEt=1:1): 0.26; HPLC: 6.44 min(System 1).

Example 761-[4-(6-Chloro-pyrimidin-4-yloxy)-phenyl]-3-(4-methyl-3-trifluoromethyl-phenyl)-urea

The title compound is synthesized in analogy to the preparation ofcompound of Example 48 starting from compound of Stage 56.1:M+H=423.1/M+18=440.1; R_(f) (CH₂Cl₂/acetone=9:1): 0.42; ¹H-NMR (400 MHz,DMSO-d₆): 8.93/8.80 (s/s, 2H, urea), 7.91 (d, 2 Hz, 1H, pyrimidinyl),7.51 (d, 9.5 Hz, 2H, phenyl), 7.47 (d, 8.0 Hz, 1H, phenyl-CF₃), 7.29 (d,8 Hz, 1H, phenyl-CF₃), 7.27 (s, 1H, phenyl-CF₃), 7.13 (d, 9.5 Hz, 2H,phenyl), 4.08 (m, 1H, pyrimidinyl), 2.63 (s/broad, 3H, CH₃);m.p.=183.0-184.5° C.

Example 771-[4-(6-Amino-pyrimidin-4-yloxy)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea

Compound of Example 56 (50 mg, 0.122 mmol) is dissolved in 2 mL EtOH and2 mL NH₃ (25% aqueous) and stirred at 80° C. in a sealed tube for 13 h.After evaporating the solvent under reduced pressure, the product isisolated by TLC (two 20×20 cm plates, 10% MeOH in CH₂Cl₂): M+H=390.0;R_(f) (CH₂Cl₂/MeOH=9:1): 0.15; ¹H-NMR (400 MHz, DMSO-d₆): 9.07/8.87(s/s, 2H, urea), 7.98 (s/broad, 1H, pyrimidinyl), 7.56 (d, 8.0 Hz, H,phenyl-CF₃), 7.47 (d, 8.0 Hz, 1H, phenyl-CF₃), 7.49 (d, 8.5 Hz, 2H,phenyl), 7.46 (s, 1H, phenyl-CF₃), 7.27 (d, 8.0 Hz, 1H, phenyl-CF₃),7.04 (d, 8.5 Hz, 2H, phenyl), 6.77 (s/broad, 2H, NH₂), 5.64 (s/broad,1H, pyrimidinyl).

Example 781-[4-(2-Chloro-pyrimidin-4-yloxy)-phenyl]-3-(4-ethyl-phenyl)-urea

The title compound is synthesized in analogy to the preparation ofcompound of Example 56: M+H=369.0/371.0; R_(f) (Hexane/AcOEt=1:1): 0.31;Anal.: C, 62.20%; (61.88%); H, 4.85%; (4.65%); N, 14.73%; (15.19%).

Example 791-[4-(2-Chloro-pyrimidin-4-yloxy)-phenyl]-3-(4-piperidin-1-yl-3-trifluoromethyl-phenyl)-urea

The title compound is synthesized in analogy to the preparation ofcompound of Example 56: M+H=491.9/493.9; R_(f) (Hexane/AcOEt=1:1): 0.38;Anal.: C, 55.67%; (56.16%); H, 4.32%; (4.30%); N, 13.62%; (14.24%).

Example 80N-(4-(6-Chloropyrimidin-4vl-oxy)-phenyl)-N′-(4-tert-butylphenyl)-urea

To a solution of 4-(6-chloro-pyrimidin-4-yl-oxy)-aniline (Stage 21.1;3.77 g, 15 mmol) in THF (55 ml) under N₂-atmosphere, 4-tertbutylphenylisocyanate (5.26 g, 30 mmol) dissolved in THF (5 ml) is added. Duringstirring for 1 h at rt a suspension is formed. The mixture is thenre-dissolved in AcOEt and a solution of NaHCO₃ in water, the aqueouslayer separated off and extracted twice with AcOEt. The organic phasesare washed with water and brine, dried (Na₂SO₄) and concentrated invacuo. Stirring of the resulting solid in Et₂O finally yields the titlecompound: m.p.: 111-112° C.; ¹H-NMR (DMSO-d₆): 8.75 (s, HN), 8.65 (s,1H), 8.62 (s, HN), 7.51 (d, 2H), 7.36 (d, 2H), 7.33 (s, 1H), 7.31 (d,2H), 7.17 (d, 2H), 1.27 (Me₃C).

Example 81N-(4-(6-Chloropyrimidin-4yl-oxy)phenyl)-N′-(4-chloro-3-trifluoromethyl-phenyl)-urea

To a solution of 4-(6-chloro-pyrimidin-4-yl-oxy)-aniline (Stage 21.1;3.77 g, 15 mmol) in THF (40 ml) under N₂-atmosphere,4-chloro-3-trifluoromethylphenyl isocyanate (4.98 g, 22.5 mmol)dissolved in THF (20 ml) is added. After 1 h at rt the solution isdiluted with AcOEt and NaHCO₃ in water, the aqueous layer separated offand extracted twice with AcOEt. The organic phases are washed with waterand brine, dried (Na₂SO₄) and concentrated in vacuo. Stirring of theresulting solid in Et₂O finally yields the title compound: m.p.:180-181° C.; ¹H-NMR (DMSO-d₆): 9.22 (s, HN), 8.97 (s, HN), 8.65 (s, 1H),8.11 (s, 1H), 7.65 (m, 1H), 7.63 (m, 1H), 7.53 (d, 2H), 7.34 (s, 1H),7.19 (d, 2H); Anal.: CHNClFO.

Example 82N-(4-(4-Methylaminopyrimidin-6-yl-oxy)-phenyl)-N′-(4-tert-butylphenyl)-urea

Under N₂-atmosphere, a solution ofN-(4-(4-chloropyrimidin-6-yl-oxy)-phenyl)-N′-(4-tert-butylphenyl)-urea(319 mg, 0.80 mmol) in methylamine/ethanol (8.03 M; 5 ml) is stirred for50 min at 40° C. Then the reaction mixture is concentrated in vacuo, theresidue re-dissolved in water and AcOEt, the aqueous layer separated offand extracted twice with AcOEt. The organic phases are washed with waterand brine, dried (Na₂SO₄) and concentrated in vacuo after adding 2 9 ofSiO₂. The resulting powder is put on top of a SiO₂-column and elutedwith AcOEt/hexane 9:1, yielding the title compound: m.p.: 245-246° C.;¹H-NMR (DMSO-d₆): 8.7 (s, HN), 8.6 (s, HN), 8.13 (s, 1H), 7.45 (d, 2H),7.35 (d, 2H), 7.31 (d, 2H), 7.05 (d, 2H), 6.78 (s, HN), 5.79 (s, 1H),2.83 (MeN), 1.30 (Me₃C).

Example 83N-(4-(4-Benzylaminopyrimidin-6-yl-oxy)-phenyl)-N′-(4-tert-butylphenyl)-urea

Under N₂-atmosphere, a suspension ofN-(4-(4-chloropyrimidin-6-yl-oxy)-phenyl)-N′-(4-tert-butylphenyl)-urea(397 mg, 1.00 mmol) and benzylamine (327 μM) in isopropanol (3 ml) isstirred for 21 h at 70° C. Then the reaction mixture is concentrated invacuo, the residue re-dissolved in saturated NaHCO₃ solution and AcOEt,the aqueous layer separated off and extracted twice with AcOEt. Theorganic phases are washed with water and brine, dried (Na₂SO₄) andconcentrated. The crude product is dissolved in CH₂Cl₂ and afteraddition of SiO₂ again concentrated. The resulting powder is put on topof a SiO₂-column and eluted with AcOEt/hexane 3:1, yielding the titlecompound: m.p.: 118-120° C.; ¹H-NMR (DMSO-d₆): 8.73 (s, HN), 8.62 (s,HN), 8.13 (s, 1H), 7.84 (s, HN), 7.46 (d, 2H), 7.35 (d, 2H), 7.30 (m,4H), 7.28 (m, 2H), 7.24 (m, 1H), 7.03 (d, 2H), 5.78 (s, 1H), 4.49 (s,2H), 1.26 (Me₃C).

Example 84N-(4-(4-Aminopyrimidin-6-yl-oxy)phenyl)N′-(4chloro-3-trifluoromethyl-phenyl)-urea

In a sealed tube under N₂-atmosphere,N-(4-(4-chloropyrimidin-6-yl-oxy)-phenyl)-N′-(4-chloro-3-trifluoromethyl-phenyl)-urea(443 mg, 1.00 mmol) and 25% aqueous NH₃ (2 ml) in ethanol (2 ml) isstirred for 22 h at 80° C. Then the reaction mixture is diluted withwater and AcOEt, the aqueous layer separated off and extracted 3 timeswith AcOEt. The organic phases are washed with 3 portions of water andbrine, dried (Na₂SO₄) and concentrated. Column chromatography (SiO₂;CH₂Cl₂/MeOH 9:1) yields the title compound: m.p.: 197-198° C.; ¹H-NMR(DMSO₆): 9.20 (s, HN), 8.93 (s, HN), 8.12 (m, 1H), 8.08 (s, 1H), 7.63(m, 2H), 7.51 (d, 2H), 7.08 (d, 2H), 6.82 (s, H₂N), 5.67 (s, 1H).

Example 85N-(4-(4-Chloropyrimidin-6-yl-oxy)-phenyl)-N′-(3-methoxy-4-piperidin-1-yl-phenyl)-urea

A solution of triphosgene (1.4 g, 4.7 mmol) in CH₂Cl₂ (95 ml) underN₂-atmosphere is cooled by an ice bath.3-Methoxypiperidin-1-yl-phenylamine (Stage 85.1; 2.95 g, 14.3 mmol) andNEt₃ (2.0 ml; 14.3 mmol) in CH₂Cl₂ (48 ml) is then added dropwise andthe resulting suspension stirred for 20 min at rt. Then a solution of4-(6-chloro-pyrimidin-4-yl-oxy)-aniline (Stage 21.1; 3.17 g, 14.3 mmol)and NEt₃ (2.0 ml; 14.3 mmol) in CH₂Cl₂ (48 ml) is added dropwise,whereby a brown solution is formed, which is stirred for 4.5 h at rt.The reaction mixture is added to saturated NaHCO₃ solution (0.3 L) andextracted with CH₂Cl₂. The organic phase is washed with water and brine,dried (Na₂SO₄) and concentrated. The crude product is dissolved inAcOEt/methanol, SiO₂ is then added and the solvent evaporate off invacuo. The resulting powder is put on top of a chromatography column(SiO₂; AcOEt/hexane 4:1) and the title compound eluted with AcOEt/hexane4:1: m.p.: 175° C.; ¹H-NMR (DMSO-d₆): 8.68 (s, 1H), 8.62 (s, 1H), 8.50(s, 1H), 7.50 (d, 2H), 7.30 (s, 1H), 7.13 (m, 3H), 6.85 (d, 1H), 6.77(d, 1H), 3.75 (s, 3H), 2.82 (m, 4H), 1.60 (m, 4H), 1.49 (m, 2H).

The starting materials are prepared as follows:

Stage 85.1: 3-Methoxy-4-piperidin-1-yl-phenylamine

1-(2-Methoxy-4-nitro-phenyl)-piperidine (Stage 85.2; 4.0 g, 17 mmol) inethanol/THF 5:1 (90 ml) is hydrogenated in the presence of Pd/C 10 %(“Engelhard 4505”; 0.4 g). Then the catalyst is filtered off and thefiltrate is concentrated yielding the title compound: ¹H-NMR (DMSO-d₆):6.58 (d, 1H), 6.19 (d, 1H), 6.04 (dd, 1H), 4.66 (s, H₂N), 3.65 (s,H₃CO), 2.70 (m, 4H), 1.56 (m, 4H), 1.43 (m, 2H).

Stage 85.2: 1-(2-Methoxy-4-nitro-phenyl)-piperidine

2-Bromo-5-nitroanisole (5.0 g, 21.5 mmol) and piperidine (8.5 ml) isstirred for 5 h at 105° C. under N₂-atmosphere. Water (80 ml) is addedand the mixture is extracted twice with CH₂Cl₂ (2×80 ml). The organicphases are washed with water and brine, dried (Na₂SO₄) and concentrated.The crude product is dissolved in AcOEt, SiO₂ is then added and thesolvent evaporate off In vacuo. The resulting powder is put on top of achromatography column (SiO₂; AcOEt/hexane 9:1) and the title compoundeluted with hexane/AcOEt 9:1→4:1: MS: [M+1]⁺=237; R_(f)=0.2(AcOEt/hexane 9:1).

Example 86N-(4-(6-Chloropyrimidin-4-yl-oxy)phenyl)-N′-(4-(4-ethyl-piperazin-1-yl)-3-methoxy-phenyl)-urea

The title compound is prepared from4-(4-ethyl-piperazin-1-yl)-3-methoxy-phenylamine (Stage 86.1; 3.99 g,16.5 mmol) and 4-(6-chloro-pyrimidin-4-yl-oxy)-aniline (Stage 21.1; 3.67g, 16.5 mmol) analogously to Example 85: m.p.: 170-171° C.; ¹H-NMR(DMSO-d₆): 8.67 (s, 1H), 8.61 (s, 1H), 8.52 (s, 1H), 7.48 (d, 2H), 7.28(s, 1H), 7.15 (d, 1H), 7.12 (d, 2H), 6.84 (d, 1H), 6.77 (d, 1H), 3.74(s, 3H), 2.86 (m, 4H), 2.44 (m, 4H), 2.33 (q, 2H), 0.98 (t, H₃C); Anal.:CHNCl.

The starting materials are prepared as follows:

Stage 86.1: 4-(4-Ethyl-piperazin-1-yl-3-methoxy-phenylamine

1-Ethyl-4-(2-methoxy-4-nitro-phenyl)-piperazine (Stage 86.2; 2.89 g, 11mmol) in ethanol/THF 5:1 (70 ml) is hydrogenated in the presence of Pd/C10% (“Engelhard 4505”; 0.3 g). Then the catalyst is filtered off and thefiltrate is concentrated yielding the title compound: ¹H-NMR (CD₃OD):6.79 (d, 1H), 6.44 (d, 1H), 6.29 (dd, 1H), 3.80 (s, H₃CO), 2.97 (m, 4H),2.65 (m, 4H), 2.52 (q, 2H), 1.14 (t, H₃C).

Stage 86.2: 1-Ethyl-4-(2-methoxy-4-nitro-phenyl)-piperazine

2-Bromo-5-nitroanisole (4.7 g, 20 mmol) and N-ethyl-piperazin (10.3 ml)is stirred for 13 h at 110° C. under N₂-atmosphere. Water (80 ml) isadded and the mixture extracted twice with CH₂Cl₂ (2×80 ml). The organicphases are washed with water and brine, dried (Na₂SO₄) and concentrated.Column chromatography (SiO₂; CH₂Cl₂/MeOH 19:1→9:1) gives the titlecompound: m.p.: 84-85° C.

Example 87N-(4-(4-Chloropyrimidin-6-yl-oxy)-phenyl)-N′-(3-methoxy-4-(piperidin-1-ylmethyl)-phenyl)-urea

The title compound is prepared from3-methoxy(piperidin-1-ylmethyl)phenylamine (Stage 87.1) and4-(6-chloro-pyrimidin-4-yl-oxy)-aniline (Stage 21.1) analogously toExample 85: MS: [M+1]⁺=468.

The starting materials are prepared as follows:

Stage 87.1: 3-Methoxy-4-(piperidin-1-ylmethyl)-phenylamine

Hydrogenation of 1-(2-methoxy-4-nitro-benzyl)-piperidine (Stage 87.2) inTHF with Raney Nickel as catalyst affords the title compound: MS:[M+1]⁺=221.

Stage 87.2: 1-(2-Methoxy-4-nitro-benzyl)-piperidine

(2-Methoxy-4-nitro-phenyl)-piperidin-1-yl-methanone (Stage 87.3; 200 mg,0.76 mmol) is dissolved in THF (8 ml) at −20° C. DIBAH (1 M in THF: 2.3ml) then is added. After 90 min at −20° C., another portion of DIBAH(0.8 ml) is added and stirring continued for 2 h. Then the reactionmixture is hydrolysed by water (30 ml) and a saturated solution ofsodium potassium tartrate (25 ml) and extracted 3 times with AcOEt. Theorganic phases are washed with brine, dried (Na₂SO₄) and concentrated.The crude product is dissolved in AcOEt, SiO₂ is then added and thesolvent evaporate off in vacuo. The resulting powder is put on top of achromatography column (SiO₂; AcOEt) and the title compound eluated withAcOEt: ¹H-NMR (DMSO-d₆): 7.83 (dd, 1H), 7.73 (d, 1H), 7.60 (d, 1H), 3.91(s, H₃CO), 3.49 (s, 2H), 2.36 (m, 4H), 1.52 (m, 4H), 1.39 (m, 2H).

Stage 87.3: (2-Methoxy-4-nitro-phenyl)-piperidin-1-yl-methanone

To an ice-cooled suspension of 2-methoxy-4-nitro-benzoic acid (5.915 g,30 mmol) in acetonitrile (50 ml) and CH₂Cl₂ (40 ml) under N₂-atmosphere,TPTU (8.912 g, 30 mmol) and NEt₃ (8.36 ml, 60 mmol) is added. Afterstirring for 40 min, piperidine (3.26 ml, 33 mmol) is added and thereaction mixture is slowly warmed up to rt. After 16 h, AcOEt (0.5 L),water (0.4 L) and saturated NaHCO₃ solution (0.2 L) is added, theaqueous phase separated off and extracted 3× with AcOEt. The organiclayers are washed with 10% citric acid solution, water and brine, dried(Na₂SO₄) and concentrated. Crystallization from AcOEt/hexane yields thetitle compound: m.p.: 104° C.; ¹H-NMR (DMSO-d₆): 7.88 (dd, 1H), 7.84 (d,1H), 7.47 (d, 1H), 3.93 (s, H₃C), 3.7-3.5 (m, 2H), 3.07 (m, 2H),1.64-1.5 (m, 4H), 1.42 (m, 2H).

Example 88

The following compounds can be prepared analogously to the describedprocedures (Table 7): TABLE 7

Reaction- conditions m.p. [° C.] MS [M + 1]⁺ Anal. a)

EtOH 20 h, rt 153-156 406 b)

neat 20 h, rt 184-185 420 c)

NH₃ 25% in H₂O; dioxane; 12 h, 80° C. 117-118 378 d)

neat 2 h, 40° C. 107-108 498 e)

isopropanol 12 h, 60° C. 96-97 518 f)

isopropanol 24 h, 80° C. 129-130 475 g)

isopropanol 29 h, 85° C. 215-216 502 h)

i)

EtOH 8 h, 40° C. 208-209 438 j)

EtOH 20 h, rt 154-156 452 k)

neat 20 h, rt 220-221 466 l)

isopropanol 17 h, 60° C. 178-179 544 m)

isopropanol 4 h, 60° C. 92-93 564 n)

isopropanol 24 h, 80° C. 126-128 521 o)

isopropanol 26 h, 85° C. 152-154 548 p)

EtOH 90 min, 50° C. 191-192 449 CHN q)

EtOH 20 h, rt 189-191 463 CHN r)

THF/isopropanol Nal 60 h, 60° C. 532 s)

isopropanol 8 h, 60° C. 575 t)

5 h rt 191-192 475 CHN u)

v)

EtOH 1 h, rt 178-180 478 w)

EtOH 11 h, rt 492 x)

isopropanol 19 h, 50° C. 604 y)

isopropanol 15 h, 70° C. 189-190 614 CHN z)

aa)

ab)

EtOH, Nal 100 min, 40° C. 477 ac)

Isopropanol/ THF Nal cat., 50° C. 589

Example 89(±)-trans-N-(4-(4-Ethylaminopyrimidin-6-yl-oxy)-phenyl)-N′-(2-phenyl-cyclopropyl)-urea(Method A)

To a solution of 4-(4-ethylaminopyrimidin-6-yl-oxy)-aniline (Stage 89.1;271 mg, 1.177 mmol) In THF (5 ml) under N₂-atmosphere,trans-2-phenyl-cyclopropyl-isocyanate (188 mg, 1.18 mmol; Aldrich) Isadded. Then the solution is stirred for 8 h, whereas a precipitate isformed. Filtration and washing with THF and ether yields the titlecompound: m.p.: 205-206° C.; ¹H-NMR (DMSO-d₆): 8.50 (s, HN), 8.11 (s,1H), 7.42 (d, 2H), 7.27 (m, 3H), 7.15 (m, 3H), 7.01 (d, 2H), 6.67 (s,HN), 5.67 (s, 1H), 3.25 (m, 2H), 2.74 (m, 1H), 1.98 (m, 1H), 1.17 (m,2H), 1.09 (t, 3H); Anal.: CHN.

The starting materials are prepared as follows:

Stage 89.1: 4-(4-Ethylaminopyrimidin-6-yl-oxy)aniline

A suspension of 4-(6-chloro-pyrimidin-4-yl-oxy)-aniline (Stage 21.1; 5.0g, 22.6 mmol) in ethylamine dissolved in ethanol (≈35%; 5 ml) underNratmosphere is stirred for 16 h at rt. Then the resulting brownsolution is diluted with water and AcOEt, the aqueous layer separatedoff and extracted twice with AcOEt. The organic phases are washed with 3portions of water and brine, dried (Na₂SO₄) and concentrated.Re-crystallisaton from boiling AcOEt gives the title compound: m.p.:143-145° C.; ¹H-NMR (CDCl₃): 8.24 (s, 1H), 7.24 (s, HN), 6.91 (d, 2H),6.69 (d, 2H), 5.63 (s, 1H), 4.97 (s, H₂N), 3.25 (m, 2H), 1.25 (t, 3H).More product can be isolated from the filtrate of the re-crystallizationby column chromatography (SiO₂; AcOEt→AcOEt/EtOH 19:1).

Example 90N-(4-(4-Ethylaminopyrimidin-6-yl-oxy)-phenyl)-N′[(R)-5-bromo-indan-2-yl]-urea(Method B)

A solution of triphosgene (117 mg, 0.393 mmol) in CH₂Cl₂ (12 ml) underN₂-atmosphere is cooled by an ice bath. A solution of[(R)-5-bromo-indan-2-yl-amine (250 mg, 1.178 mmol; preparation see Adv.Synth. Catal. 2001, 343, 461) and NEt₃ (164 μl; 1.177 mmol) in CH₂Cl₂(10 ml) is added dropwise, the dropping funnel rinsed with CH₂Cl₂ (2 ml)and the resulting suspension stirred for 60 min at rt. Then a solutionof 4-(4-ethylaminopyrimidin-6-yl-oxy)-aniline (258 mg, 1.12 mmol) andNEt₃ (164 μl; 1.177 mmol) in CH₂Cl₂ (10 ml) is added dropwise and thedropping funnel rinsed with CH₂Cl₂ (2 ml). A brown solution is formed,which is stirred for 16 h at rt. SiO₂ is then added to the resultingmixture. After concentration in vacuo, the powder is put on top of aMPLC column (SiO₂). Eluation with SiO₂/AcOEt 4:1→AcOEt, partialconcentration and filtration of the crystallized material yields thetitle compound: m.p.: 247° C.; ¹H-NMR (DMSO-d₆): 8.33 (s, 1H), 8.06 (s,1H), 7.43 (s, 1H), 7.36 (d, 2H), 7.30 (m, 1H), 7.26 (t, 1H), 7.19 (d,1H), 6.96 (d, 2H), 6.43 (d, 1H), 5.63 (s, 1H), 4.40 (m, 1H), 3.2 (m,4H), 2.75 (AB×d, 2H), 1.07 (t, 3H); Anal.: CHNBr.

Example 91

The following compounds can be prepared analogously to the describedprocedures (Table 8): TABLE 8

Reaction- conditions m.p. [° C.] MS [M + 1]⁺ Anal. a)

A: THF; 16 h, rt 230-232 378 CHN b)

A: THF; 16 h, rt 222 378 CHN c)

A: THF; 6 h, rt 226-227 378 CHN d)

A: THF; 16 h, rt 209-210 350 CHN e)

A: THF; 8 h, rt 224 394 f)

B: CH₂Cl₂, Et₃N 241 390 CHN g)

B: CH₂Cl₂, Et₃N 243-244 468/470 h)

B: CH₂Cl₂, Et₃N 208-210 450

Example 92N-(4-(2-Methoxypyridin-4-yl-oxy)-phenyl)-N′-(4-ethyl-phenyl)-urea

The title compound is prepared from4-(4-amino-phenoxy)-2-methoxy-pyridine (Stage 92.1; 91 mg, 0.42 mmol)and 4-ethyl-phenyl-isocyanate (124 μl, 0.84 mmol) analogously to Example89: m.p.: 196° C.; Anal.: CHN.

The starting materials are prepared as follows:

Stage 92.1: 4-(4-Amino-phenoxy)-2-methoxy-pyridine

Hydrogenation of 2-methoxy-4-(4-nitro-phenoxy)pyridine (Stage 92.2; 0.12g, 0.5 mmol) in AcOEt (10 ml) in the presence of Raney Nickel (20 mg)affords after filtration and concentration of the filtrate the titlecompound: ¹H-NMR (CDCl₃): 7.97 (d, 1H), 6.86 (d, 2H), 6.67 (d, 2H), 6.48(d, 1H), 6.13 (s, 1H), 3.89 (s, H₃CO), 3.70 (s, H₂N).

Stage 92.2: 2-Methoxy-4-(4-nitro-phenoxy)-pyridine (A) and1-methyl-4-(4-nitro-phenoxy)-1H-pyridin-2-one (B)

In a sealed tube under N₂-atmosphere,4-(4-nitro-phenoxy)-1H-pyridin-2-one (Stage 92.3; 800 mg, 3.45 mmol),Ag₂CO₃ (552 mg, 2.0 mmol), methyl-iodide (474 μl, 7.6 mmol) andacetonitrile (70 ml) are stirred for 16 h at 60° C. The reaction mixtureis filtered through Celite, the filtrate concentrated andchromatographed (SiO2; AcOEt) yielding (A) followed by (B): ¹H-NMR(DMSO-d₆) (A): 8.32 (d, 2H), 8.18 (d, 1H), 7.37 (d, 2H), 6.78 (d, 1H),6.49 (s, 1H), 3.86 (s, H₃CO); (B): 8.30 (d, 2H), 7.80 (d, 1H), 7.40 (d,2H), 6.15 (d, 1H), 5.80 (s, 1H), 3.40 (s, H₃CO).

Stage 92.3: 4-(4-Nitro-phenoxy)-1H-pyridin-2-one

A suspension of 2,4-dihydroxy-pyridine (2.33 g, 21 mmol),4-fluoro-nitrobenzene (2.22 ml, 21 mmol) and Cs₂CO₃ (10.2 g, 31.3 mmol)in N-methyl-pyrrolidine (30 ml) is stirred for 3 h at 100° C. underN₂-atmosphere. The reaction mixture is poured into water and theprecipitate filtered off and washed with water. The solid is dissolvedin CH₂Cl₂/MeOH. Then SiO₂ (≈20 g) is added and the mixture Isconcentrated in vacuo. The resulting powder is put on top of aSiO₂-column and eluted with toluene/AcOEt 3:1→AcOEt→AcOEt/EtOH 9:1,yielding the title compound: m.p.: 227-228° C.; ¹H-NMR (DMSO-d₆): 11.60(s, HN), 8.31 (d, 2H), 7.47 (d, 1H), 7.39 (d, 2H), 6.07 (dd, 1H), 5.67(d, 1H).

Example 93N-(4-(1-H-6-oxo-1,6-dihydro-pyridin-3-yl-oxy)-phenyl)-N′-(4-tert-butyl-phenyl)-urea

The title compound Is prepared from 3-(4-amino-phenoxy)-1H-pyridin-6-one(Stage 93.1; 1.00 mmol) and 4-tert-butyl-phenyl-isocyanate (346 μl, 2.0mmol) In THF (10 ml) analogously to Example 89: m.p.: 234° C.; Anal.:CHN.

The starting materials are prepared as follows:

Stage 93.1: 3-(4-amino-phenoxy)-1H-pyridin-6-one

Hydrogenation of 3-(4-nitro-phenoxy)-1H-pyridin-6-one (Stage 93.2; 464mg, 2.0 mmol) in DMEU (10 ml) in the presence of Raney Nickel (100 mg)affords after filtration and concentration of the filtrate the titlecompound: ¹H-NMR (DMSO-d₆): 11.2 (s, HN), 7.25 (dd, 1H), 7.11 (d, 1H),6.68 (d, 2H), 6.51 (d, 2H), 6.35 (d, 1H), 4.87 (s, H₂N).

Stage 93.2: 3-(4-Nitro-phenoxy)-1H-pyridin-6-one

A suspension of 2,5-dihydroxy-pyridine (4.65 g, 41.9 mmol),4-fluoro-nitrobenzene (2.22 ml, 21 mmol) and Cs₂CO₃ (13.7 g, 41.9 mmol)in N-methyl-pyrrolidine (60 ml) is stirred for 18 h at 90° C. underN₂-atmosphere. The reaction mixture is diluted with water and AcOEt, theaqueous layer separated off and extracted twice with AcOEt. The organicphases are washed with a NaHCO₃ solution and brine, dried (Na₂SO₄) andpartially concentrated. Thereby the title compound crystallizes and canbe filtered off and washed with AcOEt: m.p.: 214-217° C.; ¹H-NMR(DMSO-d₆): 11.6 (s, HN), 8.22 (d, 2H), 7.57 (d, 1H), 7.43 (dd, 1H), 6.14(d, 2H), 6.46 (d, 1H).

Example 94

The following compounds can be prepared analogously to the describedprocedures (Table 9):

m.p. [° C.] MS [M + 1]⁺ Anal. a)

390 b)

257-260 336 c)

238-241 350 d)

228-229 424 CHNFCl

Example 95N-(4-(6-Methoxy-pyridin-3-ylmethyl)-phenyl)-N′-(4-methyl-phenyl)-urea

The title compound is prepared from4-(6-methoxy-pyridin-3-ylmethyl)-phenylamine (Stage 95.1; 300 mg, 1.40mmol) and 4-methyl-phenyl-isocyanate (0.35 ml, 2.8 mmol) in THF (11 ml)analogously to Example 89: ¹H-NMR (DMSO-d₆): 8.68 (s, 2 HN), 8.02 (d,1H), 7.49 (dd, 1H), 7.33 (d, 2H), 7.29 (d, 2H), 7.09 (d, 2H), 7.03 (d,2H), 6.70 (d, 1H), 3.79 (2s, 5H), 2.21 (s, 3H).

The starting materials are prepared as follows:

Stage 95.1: 4-(6-methoxy-pyridin-3-ylmethyl)-phenylamine

Rac-(6-methoxy-pyridin-3-yl)-(4-nitro-phenylymethanol (Stage 95.2; 5.4g, 21 mmol) in methanol (0.3 L) is hydrogenated with Pd/C 10%(“Engelhard 4505”; ≈5 g) as catalyst for 3 days under 1 atmosphereH₂-pressure. Then the catalyst is filtered off, the filtrateconcentrated and chromatographed (SiO₂; hexane/AcOEt 3:2→1:1) yieldingthe title compound: ¹H-NMR (CDCl₃): 7.99 (d, 1H), 7.34 (dd, 1H), 6.95(d, 2H), 6.65 (d, 1H), 6.62 (d, 2H), 3.93 (s, H₃CO), 3.78 (s, 2H), 3.6(sb, H₂N).

Stage 95.2: Rac-(6-methoxy-pyridin-3-yl)-(4-nitro-phenyl)methanol

A solution of n-butyl-lithium (1.6 m in hexane; 28 ml, 44.8 mmol) inether (40 ml) is cooled down to −50° C. in a dried vessel under anatmosphere of N₂. Then a solution of 5-bromo-2-methoxy-pyridine (5.7 ml,44 mmol) in ether (48 ml) is added dropwise, whereby a yellowishsuspension is formed, and the reaction mixture stirred for 1 h at −50°C. In a second vessel, 4-nitro-benzaldehyde (6.04 g, 40 mmol) in THF (60ml) is prepared at −60° C. Then the yellowish suspension of5-lithio-2-methoxy-pyridine Is transferred via canula into the secondvessel. After 30 min stirring at −40° C., a mixture of water (20 ml) andsaturated NH₄Cl-solution (10 ml) is added. The resulting mixture ispoured into water and AcOEt, the aqueous layer separated off andextracted twice with AcOEt. The organic phases are washed with water andbrine, dried (Na₂SO₄) and concentrated. Column chromatography (SiO₂;hexane/AcOEt 3:1→2:1) yields the title compound: m.p.: 142° C.; ¹H-NMR(CDCl₃): 8.20 (d, 2H), 8.15 (dd, 1H), 7.57 (d, 2H), 7.47 (dd, 1H), 6.73(d, 1H), 5.91 (d, 1H), 3.93 (s, H₃CO), 2.50 (s, HO).

Example 96N-(4-(6-Oxo-1,6-dihydro-pyridin-3-ylmethyl)-phenyl)-N′-(4-methyl-phenyl)-urea

A suspension ofN-(4-(6-methoxy-pyridin-3-ylmethyl)-phenyl)-N′-(4-methyl-phenyl)-urea(Example 95; 0.28 g, 0.81 mmol) and trimethylsilyl-jodide (0.6 ml) inchloroform (10 ml) is stirred for 16 h at 60° C. Then CH₂Cl₂ (4 ml),water (10 ml) and saturated NaHCO₃ solution (5 ml) is added and thesuspension stirred vigorously. Filtration, washing with CH₂Cl₂ and waterfollowed by column chromatography (SiO₂; AcOEt/MeOH 9:1→4:1 MeOH) yieldsthe title compound: ¹H-NMR (DMSO-d₆): 11.4 (s, HN), 8.52 (s, HN), 8.47(s, HN), 7.33 (d, 2H), 7.29 (d, 2H), 7.25 (dd, 1H), 7.16 (s, 1H), 7.07(d, 2H), 7.04 (d, 2H), 6.24 (d, 1H), 3.58 (s, 2H), 2.22 (s, 3H).

Example 97 1-[4-(6-Chloro-pyrimidin-4-yloxy)-phenyl]-3-p-tolyl-urea

4-(6-Chloro-pyrimidin-4-yloxy)-phenylamine (331 mg, 1.50 mmol) isdissolved in DMF (3 mL) under an argon atmosphere at rt. Pyridine (133.2μL, 1.65 mmol) is added dropwise followed by dropwise addition ofp-tolylisocyanate (221 μL, 1.80 mmol). The reaction Is stirred for 30min at rt. The solvent is removed in vacuo and the residual crudeproduct is titurated with ethyl acetate/hexanes 9:1 to give the titlecompound as a white powder: m.p.=217-219° C.; C₁₈H₁₅N₄O₂Cl: M+=355.1;¹H-NMR (DMSO-d₆): 8.78 (s, 1H), 8.61 (s, 1H), 8.59 (s, 1H, HN), 7.52 (d,2H), 7.37 (d, 2H), 7.17 (d, 2H), 7.05 (d, 2H), 2.21 (s, 3H).

Example 981-[4-(6-Chloro-pyrimidin-4-yloxy)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea

The title compound is prepared in analogy to Example 97 and purified byflash chromatography (SiO2, gradient hexanes/ethyl acetate 7:3 to 4:6)to yield a white powder m.p.=180-183° C; ¹H-NMR (DMSO-d₆): 9.15 (s, 1H,HN), 8.90 (s, 1H, HN), 8.81 (s, 1H), 8.00 (s, 1H), 7.59-7.40 (m, 3H),7.37-7.29 (m, 2H), 7.16 (d, 2H).

Example 99 1-[4-(6-Ethyl-pyrimidin-4-yloxy)phenyl]-3-p-tolyl-urea

1-[4-(6-Chloro-pyrimidin-4-yloxy)-phenyl]-3-p-tolyl-urea (Example 97;106 mg, 0.3 mmol) is dissolved in THF (10 mL) under an argon atmosphereand CuCN (215 mg, 2.4 mmol) is added. The mixture is then cooled to −78°C. and EtMgBr (1.8 ml of a 3 M solution in THF) is added via a canula.The reaction mixture is allowed to stir for 30 min at −78° C. and thenwarmed to rt resulting in a brown suspension. It Is stirred foradditional 30 min at rt and then the solvent is removed in vacuo. Theresidual crude product is re-dissloved in CH₂Cl₂/MeOH 1:1 and purifiedby flash chromatography (SiO₂, gradient hexanes/ethyl acetate 1:1 to3:7) to give the title compound which is further purified by preparativeTLC (SiO₂, hexanes/AcOEt 3:7): m.p.=160-162° C.; C₂₀H₂₀N₄O₂: M⁺=349.1;¹H-NMR (DMSO-d₆): 9.55 (s, 1H, HN), 9.45 (s, 1H, HN), 8.64 (s, 1H), 7.55(d, 2H); 7.40 (d, 2H), 7.10-7.06 (m, 4H), 6.92 (s, 1H), 2.70 (q, 2H),2.24 (s, 3H), 1.22 (t, 3H).

The following Examples 100 a)-g) of Table 10 are prepared in analogy tothe procedure of Example 99: TABLE 10

MS Ex. R1 R2 ¹H-NMR (DMSO-d₆): m.p. [° C.] [M + 1]⁺ a) iso- 4-Me 8.99(s, 1H, HN); 8.70 (s, 1H, HN), 8.65 (s, 160-162 363.2 propyl 1H), 7.50(d, 2H), 7.34 (d, 2H), 7.19-6.99 (m, 4H), 6.95 (s, 1H), 3.12-2.95 (m,1H), 2.24 (s, 3H), 1.22 (d, 6H). b) Et 3-CF₃ 9.26 (8, 1H, HN), 9.10 (s,1H, HN), 8.63 (s, 140-142 402.9 1H), 8.02 (s, 1H), 7.58 (d, 1H),7.55-7.50 (m, 3H), 7.31 (d, 1H), 7.13 (d, 2H), 6.95 (s, 1H), 2.72 (q,2H), 1.21 (t, 3H). c) cyclo- 4-Me 8.75 (s, 1H, HN), 8.53 (s, 1H), 8.59(s, 1H, 179-181 403.1 hexyl HN), 7.48 (d, 2H), 7.33 (d, 2H), 7.19-7.00(m, 4H), 6.91 (s, 1H), 2.69-2.63 (m, 1H), 1.93-1.75 (m, 2H), 1.75-1.70(m, 1H), 1.52- 1.45 (m, 2H), 1.36-1.32 (m, 1H). d) Me 4-Me 8.77 (s, 1H,HN), 8.63 (s, 1H, HN), 8.61 (s, 180-182 335.1 1H), 7.49 (d, 2H), 7.33(d, 2H), 7.19-7.01 (m, 4H), 6.92 (s, 1H), 2.42 (s, 3H), 2.24 (s, 3H). e)cyclo- 3-CF₃ 9.24 (s, 1H, HN), 9.00 (s, 1H, HN), 8.64 (s, 149-151 457.2hexyl 1H), 8.02 (s, 1H), 7.61 (d, 1H), 7.55-7.41 (m, 3H), 7.30 (d, 1H),6.92 (s, 1H), 2.65- 6.61 (m, 1H), 1.85-1.81 (m, 2H), 1.49-1.44 (m, 2H),1.36-1.32 (m, 1H). f) iso- 3-CF₃ 9.24 (s, 1H, HN), 8.90 (s, 1H, HN),8.65 (s, 166-168 417.0 propyl 1H), 8.02 (, s1H), 7.58 (d, 1H), 7.53-7.49(m, 3H), 7.32 (d, 1H), 7.14 (d, 2H), 6.97 (s, 1H), 3.09-2.90 (m, 1H),1.22 (d, 6H). g) Me 3-CF₃ 9.20 (s, 1H, HN), 8.61 (s, 1H), 8.02 (s, 1H),149-151 389.1 7.58 (d, 1H), 7.53-7.49 (m, 3H), 7.32 (d, 1H), 7.13 (d,2H), 6.94 (s, 1H), 2.43 (s, 3H).

Example 1011-[4-(6-Acetyl-pyrimidin-4-yloxy)-phenyl-3-3(-trifluoromethylphenyl)-urea

Stage 101.1: (4-Chloro-pyridin-2-yl)-pyrrolidin-1-yl-methanone

4-Chloro-pyridine-2-carboxylic acid methylester (200 mg, 1.17 mmol) andMgCl₂ (555 mg, 0.58 mmol) are suspended in THF (5 mL) at rt. The mixtureis stirred for 5 min and then pyrrolidine (193 μL, 2.33 mmol) is addedand the mixture stirred for an additional 15 min. It is worked up byaddition of aqueous HCl solution (1M, 1.2 mL) and extraction with ethylacetate. The combined organic extracts are washed with brine dried overMgSO₄. The volatiles are removed under reduced pressure to give thetitle compound as a yellow oil: C₁₀H₁₁ClN₂O: M⁺=211.3; ¹H-NMR (DMSO-d₆):8.55 (d, 1H), 7.82 (s, 1H), 7.59 (d, 1H), 3.62-3.42 (m, 4H), 1.93-1.75(m, 4H).

Stage 101.2: [4-(4-Amino-phenoxy)-pyridin-2-yl]pyrrolidin-1-yl-methanone

4-Aminophenol (122 mg, 1.12 mmol) is dissolved in DMF (3 ml) and treatedwith potassium-tert-butylate (131 mg, 1.16 mmol) at rt. The reactionmixture is stirred for 2 h to give a brown suspension.(4-Chloro-pyridin-2-yl)-pyrrolidin-1-yl-methanone (Stage 101.1; 236 mg,1.12 mmol) and K₂CO₃ (82 mg, 0.59 mmol) are added. The reaction mixtureis then stirred for 12 h at 80° C. It Is allowed to cool to rt again andthe solvent is removed in vacuo. The residual brown oil is taken up inethyl acetate and washed with brine. The organic layer is dried overMgSO₄, concentrated and the residual crude product is purified by flashchromatography (SiO₂; gradient CH₂Cl₂/MeOH 99:1 to 92:8) to give thetitle compound as a slightly brown solid: C₁₆H₁₇N₃O₂: M⁺=284.2.

102.3:1-{4-[2-Pyrrolidine-1-carbonyl)-pyridin-4-yloxy]-phenyl}-3-p-tolyl-urea

[4-(4-Amino-phenoxy)-pyridin-2-yl]pyrrolidin-1-yl-methanone (Stage101.2; 118 mg, 0.42 mmol) is dissolved in DMF (3 mL) and cooled in anice bath. Pyridine (37 μL, 0.46 mmol) and3-(trifluoromethyl)phenyl-isocyanate (70 μL, 0.50 mmol) are added andthe reaction mixture allowed to reach rt. After 30 min it is worked upby removal of all volatiles under reduced pressure and purification ofthe residual crude product by flash chromatography (SiO₂; gradientCH₂Cl₂/MeOH 99:1 to 95:5) to give the title compound as a slightly brownsolid: C₂₄H₂₁F₃N₄O₃: M⁺=471.5; ¹H-NMR (DMSO-d₆): 9.09 (s, 1H, HN), 8.92(s, 1H, HN), 8.42 (d, 1H), 7.99 (s, 1H), 7.61-7.42 (m, 4H), 7.29 (d,1H), 7.17 (d, 2H), 7.03 (d, 1H), 7.01 (dd, 1H), 3.62-3.58 (m, 2H),3.49-3.39 (m, 2H), 1.87-1.72 (m, 4H).

Stage 101.4:1-[4-(6-Acetyl-pyrimidin-4-yloxy)-phenyl]-3-(-trifluoromethyl-phenyl)urea

1-{4-[2-Pyrrolidine-1-carbonyl)-pyridin-4-yloxy]-phenyl}-3-p-tolyl-urea(Stage 101.3; 23 mg, 0.05 mmol) is dissolved in THF (200 μL) and cooledto −78° C. Methyllithium (98 μL, 0.10 mmol, of a 1.6 M solution indiethyl ether) is added dropwise. The reaction mixture is stirred for 30min at −78° C. and then allowed to reach rt and stirred for additional 2h. It is worked up by removal of all volatiles in vacuo, the residue istaken up in ethyl acetate and washed with brine and afterwards purifiedby preparative TLC (SiO₂, hexanes/ethyl acetate 7:3) to give the titlecompound as a white solid: m.p.=149-151° C.; C₂₁H₁₆F₃N₃O₃: M⁺=416.1;¹H-NMR (DMSO-d₆): 9.36 (s, 1H), 8.99 (s, 1H), 8.60 (d, 1H), 8.02 (s,1H), 7.58 (d, 3H), 7.54-7.51 (m, 1H), 7.35-7.30 (m, 1H), 7.28-7.25 (m,1H), 7.15 (d, 2H), 2.16 (s, 3H).

Example 102 1-[4-(2-Cyano-pyridin-4-yloxy)-phenyl]-3-D-tolyl-urea

p-Tolylisocyanate (66.4 μL, 0.521 mmol, 1.1 equiv) is added to asolution of 4-(4-amino-phenoxy)-pyridine-2-carbonitrile (100 mg, 0.473mmol) in THF abs. (1.45 mL), under an argon atmosphere. The resultingmixture is stirred at rt for 2 h, diluted with 3 mL of a hexane/CH₂Cl₂(2/1) solution and filtered through a glass sintered funnel. The residueis washed with the above-mentioned solvents mixture and dried in vacuoto afford the title compound as a beige solid: ES-MS: 345.0 [M+H]⁺;single peak at t_(R)=9.04 min (System 2); R_(f)=0.19 (CH₂Cl₂/Et₂O,90/10).

4-(4-Amino-phenoxy)-pyridine-2-carbonitrile:

4-Amino-phenol (2.54 g, 22.8 mmol, 1.1 equiv) is added in one portion toa suspension of NaH (60% free-flowing powder moistened with oil, 1.25 g,31.2 mmol, 1.5 equiv) in dioxane abs. (30 mL), under an argonatmosphere. When hydrogen evolution subsides, 4-nitro-pyridine N-oxide(3 g, 20.8 mmol) is added in one portion. The resulting dark mixture isheated to 100° C. (oil bath temperature) for 22 h and then allowed tocool to rt. Me₃SiCN (3.5 mL, 27.0 mmol, 1.3 equiv) is added. After 5min, the reaction mixture is cooled with a 10° C. water bath andN,N-dimethylcarbamoyl chloride (2.5 mL, 27.0 mmol, 1.3 equiv) Is addeddropwise. The reaction mixture is allowed to warm to rt. When thereaction becomes exothermic, the water bath (10° C.) is applied for afew minutes. The reaction mixture is allowed to warm to rt, stirred for1 h, quenched by addition of MeOH (30 mL), and concentrated in vacuo.After addition of CH₂Cl₂ to the residue, the resulting suspension isfiltered through a glass sintered funnel (washing with copious amount ofthe same solvent). The filtrate is concentrated in vacuo and the residueis purified by silica gel (200 g) column chromatography (CH₂Cl₂/Et₂O,90/10) to afford the title compound as a brownish solid: ES-MS: 211.9[M+H]⁺; single peak at t_(R)=4.86 min (System 2); R_(f)=0.44(CH₂Cl₂/Et₂O, 80/20).

Example 1031-[4-(2-Cyano-pyridin-4-yloxy)-phenyl]-3-(4-ethyl-pheny)-urea

The title compound is prepared as described in Example 102 but using4ethyl-phenyl-isocyanate. After a 2.5 h stirring, the reaction mixtureis concentrated in vacuo and the residue is purified by silica gel (18g) column chromatography (CH₂Cl₂/Et₂O, 90/10) to afford the titlecompound as a beige solid: ES-MS: 359.0 [M+H]⁺; single peak att_(R)=9.41 min (System 2); R_(f)=0.22 (CH₂Cl₂/Et₂O, 90/10).

Example 1041-4-(2-Cyano-pyridin-4-yloxy)-phenyl]-3-(3-trifluoromethyl-pheny)urea

The title compound is prepared as described in Example 102 but usingα,α,α-trifluoro-m-tolyl-isocyanate. After a 3 h stirring, the reactionmixture is concentrated in vacuo and the residue is purified by silicagel (18.5 g) column chromatography (CH₂Cl₂, then CH₂Cl₂/MeOH, 99/1) toafford the title compound as a light yellow solid: ES-MS: 398.9 [M+H]⁺;single peak at t_(R)=9.54 min (System 2); R_(f)=0.067 (CH₂Cl₂/MeOH,99/1).

Example 105 1-[4-(2-Chloro-pyridin-4-yloxy)-phenyl]-3-p-tolyl-urea

The title compound is prepared as described in Example 102 but using4-(2-chloro-pyridin-4-yloxy)-phenylamine and stirring the reactionmixture for 3 h. The title compound is obtained as a white solid: ES-MS:354.0 [M+H]⁺; single peak at t_(R)=9.53 min (System 2); R_(f)=0.19(CH₂Cl₂/Et₂O, 90/10).

4-(2-Chloro-pyridin-4-yloxy)-phenylamine

4-Amino-phenol (1.05g, 9.40 mmol, 1.1 equiv) is added in one portion toa suspension of NaH (60% free-flowing powder moistened with oil, 0.513g, 12.8 mmol, 1.5 equiv) in dioxane abs. (6.5 mL), under an argonatmosphere. When hydrogen evolution subsides, a solution of2-chloro-4-nitropyridine (1.35 g, 8.54 mmol) in dioxane (6 mL) is added.The resulting dark mixture is heated to 100° C. (oil bath temperature)for 70.5 h, allowed to cool to rt, quenched by addition of MeOH andpartially concentrated in vacuo. The oily residue is dissolved inCH₂Cl₂/MeOH (80/20) and filtered through a glass sintered funnelcontaining silica gel (18 g), eluting with CH₂Cl₂/MeOH (90/10). Thefiltrate is partially concentrated in vacuo, diluted with CH₂Cl₂/MeOH(90/10) and purified by silica gel (70 g) column chromatography(CH₂Cl₂/Et₂O, 90/10, then 85/15). A second column chromatographypurification affords the title compound as a yellow solid: ES-MS: 221.1[M+H]⁺; single peak at t_(R)=6.56 min (System 2); R_(f)=0.27(CH₂Cl₂/Et₂O, 80/20).

2-Chloro-4-nitropyridine is prepared according to a literature procedure[M. A. Walters, J. J. Shay, Tetrahedron Letters, 36 (42), 7575-7578(1995)] and used as a crude material.

Example 1061-[4-(2-Chloro-pyridin-4-yloxy)-phenyl]-3-(4-ethyl-phenyl)-urea

The title compound is prepared as described in Example 102 but using4-(2-chloro-pyridin-4-yloxy)-phenylamine (Example 105) and4-ethyl-phenyl-isocyanate. The reaction mixture is stirred for 4 h. Thetitle compound is obtained as a beige solid: ES-MS: 368.0 [M+H]⁺; singlepeak at t_(R)=9.85 min (System 2); R_(f)=0.36 (CH₂Cl₂/Et₂O, 90/10).

Example 1071-[4-(2-Chloro-pyridin-4-yloxy)-phenyl]-3-(3-trifluoromethyl-pheny)-urea

The title compound is prepared as described in Example 102 but using4-(2-chloro-pyridin-4-yloxy)-phenylamine (Example 105) andα,α,α-trifluoro-m-tolyl-isocyanate. The reaction mixture is stirred for4 h. The title compound is obtained as a beige solid: ES-MS: 407.9[M+H]⁺; single peak at t_(R)=9.99 min (System 2); R_(f)=0.30(CH₂Cl₂/Et₂O, 90/10).

Example 1081-p-Tolyl-3-[4-(2-trifluoromethyl-pyridin-4-yloxy)-phenyl]-urea

The title compound is prepared as described in Example 102 but using4-(2-trifluoromethyl-pyridin-4-yloxy)-phenylamine and stirring thereaction mixture for 4 h. The title compound is obtained as a whitesolid: ES-MS: 388.0 [M+H]⁺; single peak at t_(R)=9.00 min (System 2);R_(f)=0.28 (CH₂Cl₂/Et₂O, 90/10).

4-(2-Trifluoromethyl-pyridin-4-yloxy)-phenylamine

A suspension of 4-(4-nitro-phenoxy)-2-trifluoromethyl-pyridine (1.16 g,4.08 mmol) and Raney Nickel (0.4 9, in EtOH) in MeOH (70 mL) is stirredat rt and under a hydrogen atmosphere for 7 h. Additional Raney Nickel(tip of spatula) is then added and the reaction mixture is stirred for17 h. The mixture is filtered through a pad of celite and the filtercake is washed with copious amount of MeOH. After removal of thesolvents in vacuo, the residue is purified by silica gel (50 g) columnchromatography (CH₂Cl₂/Et₂O, 95/5) to afford the title compound as awhite solid: ES-MS: 255.0 [M+H]⁺; single peak at t_(R)=5.97 min (System2); R_(f)=0.40 (CH₂Cl₂/Et₂O, 90/10).

4-(4-Nitro-phenoxy)-2-trifluoromethyl-pyridine

A mixture of 2-trifluoromethyl-pyridin-4-ol (0.675 g, 4.14 mmol),1-fluoro-4-nitro-benzene (0.54 mL, 4.97 mmol, 1.2 equiv), and NaOH(0.203 g,4.97 mmol, 1.2 equiv) in DMF abs. is heated to 100° C. (oilbath temperature) for 21.5 h, under an argon atmosphere. The reactionmixture is allowed to cool to rt, filtered through a glass sinteredfunnel and concentrated in vacuo. The residual yellow solid is purifiedby silica gel (100 g) column chromatography (CH₂Cl₂/hexane, 70/30) toafford the title compound as a white solid: ES-MS: 285.0 [M+H]⁺; singlepeak at t_(R)=8.71 min (System 2); R_(f)=0.25 (CH₂Cl₂/hexane, 70/30).

2-Trifluoromethyl-pyridin-4-ol is prepared according to a reportedthree-step procedure [V. I. Tyvorskii, D. N. Bobrov; Chemistry ofHeterocyclic Compounds, 33 (8), 995-996 (1997)].

Example 1091-(4-Ethyl-phenyl)-3-[4-(2-trifluoromethyl-pyridin-4-yloxy)-phenyl]-urea

The title compound is prepared as described in Example 102 but using4-(2-trifluoromethyl-pyridin-4-yloxy)-phenylamine (Example 108) and4-ethyl-phenyl-isocyanate. The reaction mixture is stirred for 4.5 h.The title compound is obtained as a white solid: ES-MS: 401.9 [M+H]⁺;single peak at t_(R)=9.33 min (System 2); R_(f)=0.37 (CH₂Cl₂/Et₂O,90/10).

Example 1101-(3-Trifluoromethyl-phenyl)-3-[4-(2-trifluoromethyl-pyridin-4-yloxy)-phenyl]-urea

The title compound is prepared as described in Example 102 but using4-(2-trifluoromethyl-pyridin-4-yloxy)-phenylamine (Example 108) andα,α,α-trifluoro-m-tolyl-isocyanate. The reaction mixture is stirred for4 h. The title compound is obtained as a white solid: ES-MS: 441.8[M+H]⁺; single peak at t_(R)=9.44 min (System 2); R_(f)=0.38(CH₂Cl₂/Et₂O, 90/10).

Example 111 1-[4-(6-Fluoro-pyrimidin-4-yloxy)-phenyl]-3-p-tolyl-urea

The title compound is prepared as described in Example 102 but using4-(6-fluoro-pyrimidin-4-yloxy)-phenylamine and stirring the reactionmixture for 4 h. The title compound is obtained as a white solid: ES-MS:339.0 [M+H]⁺; single peak at t_(R)=8.20 min (System 2); R_(f)=0.18(CH₂Cl₂/Et₂O, 90/10).

4-(6-Fluoro-pyrimidin-4-yloxy)-phenylamine

4-Amino-phenol (0.135 g, 1.21 mmol) is added in one portion to asuspension of NaH (60% free-flowing powder moistened with oil, 58.2 mg,1.45 mmol, 1.2 equiv) in dioxane abs. (1.4 mL), under an argonatmosphere. When hydrogen evolution subsides, a solution of4,6-difluoro-pyrimidine (0.141 g, 1.21 mmol) in dioxane (0.4 mL) Isadded. The resulting dark mixture is stirred for 1.5 h at rt, quenchedby addition of MeOH (2 mL) and concentrated in vacuo. After addition ofCH₂Cl₂, the resulting suspension is filtered and concentrated in vacuo.The residue is purified by silica gel column chromatography(CH₂Cl₂/Et₂O, 90/10, then 85/15) to afford the title compound as a whitesolid: ES-MS: 204.0 [M+H]⁺; single peak at t_(R)=4.96 min (System 2);R_(f)=0.30 (CH₂Cl₂/Et₂O, 85/15).

4,6-Difluoro-pyrimidine

A mixture of 4,6-dichloro-pyrimidine (5 g, 33.6 mmol), potassiumfluoride (6.3 g, 107 mmol, 3.2 equiv), and tetrabutylammonium bromide(0.134 g, 0.403 mmol, 0.012 equiv) in sulfolane (22.4 mL) is heated to180-190° C. (oil bath temperature) for 3.5 h. Distillation of thereaction mixture provides the title compound as a colorless liquid:¹H-NMR (300 MHz, CDCl₃): 8.62 (s, 1H), 6.65-6.55 (m, 1H); single peak att_(R)=3.5 min (System 2).

Example 1121-(4-Ethyl-phenyl)-3-[4-(6-Fluoro-pyrimidin-4-yloxy)-phenyl]-urea

The title compound is prepared as described in Example 102 but using4-(6-fluoro-pyrimidin-4-yloxy)-phenylamine (Example 111) and4-ethyl-phenyl-isocyanate. The reaction mixture is stirred for 4 h. Thetitle compound is obtained as a white solid: ES-MS: 353.0 [M+H]⁺; singlepeak at t_(R)=8.61 min (System 2); R_(f)=0.14 (CH₂Cl₂/Et₂O, 90/10).

Example 1131-[4-(6-Fluoro-pyrimidin-4-yloxy)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea

The title compound is prepared as described in Example 102 but using4-(6-fluoro-pyrimidin-4-yloxy)-phenylamine (Example 111) andα,α,α-trifluoro-m-tolyl-isocyanate. The reaction mixture is stirred for4 h. The title compound is obtained as a white solid: ESMS: 392.9[M+H]⁺; single peak at t_(R)=8.90 min (System 2); R_(f)=0.14(CH₂Cl₂/Et₂O, 90/10).

Example 1141-p-Tolyl-3-[4-(6-trifluoromethyl-pyrimidin-4-yloxy)-phenyl]-urea

The title compound is prepared as described In Example 102 but using4(6-trifluoromethyl-pyrimidin-4-yloxy)phenylamine and stirring thereaction mixture for 4 h. The product is recovered by vacuum filtrationthrough a glass sintered funnel, washed with THF and dried In vacuo toafford the title compound as a white solid: ES-MS: 389.0 [M+H]⁺; singlepeak at t_(R)=9.38 min (System 2).

4-(6-Trifluoromethyl-pyrimidin-4-yloxy)-phenylamine

4-Amino-phenol (1.2 g, 10.9 mmol) is added in one portion to asuspension of NaH (60% free-flowing powder moistened with oil, 0.48 g,12.0 mmol, 1.1 equiv) in dioxane abs. (18 mL), under an argonatmosphere. When hydrogen evolution subsides, a solution of4-chloro-6-trifluoromethyl-pyrimidine (2.0 g, 10.9 mmol) in dioxane (2.0mL) is added. The resulting dark mixture is heated to 60-65° C. (oilbath temperature) for 40 min, allowed to cool to rt, quenched byaddition of MeOH and concentrated in vacuo. The residue is purifiedtwice by silica gel (200 g) column chromatography (CH₂Cl₂/MeOH, 99/1,then 98/2) to afford the title compound as a white solid: ES-MS: 256.0[M+H]⁺; single peak at t_(R)=6.35 min (System 2); R_(f)=0.33(CH₂Cl₂/MeOH, 98/2).

4-Chloro-6-trifluoromethyl-pyrimidine is prepared according to aliterature procedure (Kanne, David B.; Prisbylla, Michael P.: U.S. Pat.No. 5,714,438 A, 1998).

Example 1151-(4-Ethyl-phenyl)-3-[4-(6-trifluoromethyl-pyrimidin-4-yloxy)-phenyl]-urea

The title compound is prepared as described in Example 102 but using4-(6-trifluoromethyl-pyrimidin-4-yloxy)-phenylamine (Example 114) and4-ethyl-phenyl-isocyanate. The reaction mixture is stirred for 2.5 h.The title compound is obtained as a white solid: ES-MS: 403.0 [M+H]⁺;single peak at t_(R)=9.72 min (System 2).

Example 1161-(3-Trifluoromethyl-phenyl)-3-[4-(6-trifluoromethyl-pyrimidin-4-yloxy)-phenyl]-urea

The title compound is prepared as described in Example 102 but using4-(6-trifluoromethyl-pyrimidin-4-yloxy)-phenylamine (Example 114) andα,α,α-trifluoro-m-tolyl-isocyanate. The reaction mixture is stirred for2.5 h. The title compound is obtained as a white solid: ES-MS: 442.9[M+H]⁺; single peak at t_(R)=9.83 min (System 2).

Example 1171-[4-(6-Chloro-pyrimidin-4-ylmethyl)-phenyl]-3-(4-ethyl-phenyl)-urea

A 4 N solution of HCl in dioxane (1.2 mL, 4.96 mmol, 30 equiv) is addedto a solution of [4-(6-chloro-pyrimidin-4-ylmethyl)-phenyl]-carbamicacid tert-butyl ester (50 mg, 0.156 mmol) in CH₂Cl₂ (0.67 mL), under anargon atmosphere. The resulting white suspension is stirred at rt for 4h and concentrated in vacuo to afford 50.9 mg of crude4-(6-chloro-pyrimidin-4-ylmethyl)-phenylamine as a white solid. DIEA (80μL, 0.454 mmol, 2 equiv) is added to a suspension of crude4-(6-chloro-pyrimidin-4-ylmethyl)-phenylamine (50 mg, 0.227 mmol) in THF(0.4 mL), under an argon atmosphere. 4-Ethyl-phenyl-isocyanate (40 μL,0.250 mmol, 1.1 equiv) is then added. The resulting yellow solution isstirred at rt for 2 h and concentrated in vacuo. The residue is purifiedby silica gel (20 g) column chromatography (CH₂Cl₂/MeOH, 98/2). A secondpurification affords the title compound as a white solid: ES-MS: 367.0[M+H]⁺; single peak at t_(R)=8.94 min (System 2); R_(f)=0.32(CH₂Cl₂/MeOH, 95/5).

[4-(6Chloro-pyrimidin-4-ylmethyl)-phenyl]-carbamic acid tert-butyl ester

Triethylamine hydrochloride (0.93 g 6.60 mmol), N,N-dimethylaniline (0.8mL, 6.60 mmol), and POCl₃ (3.7 mL, 39.6 mmol, 6 equiv) are addedsequentially to a solution of[4-(6-hydroxy-pyrimidin-4-ylmethyl)-phenyl]-carbamic acid tert-butylester (2.0 g, 6.60 mmol) in CH₃CN (16.5 mL), at rt and under an argonatmosphere. The resulting yellow solution is stirred at rt for 1 h andthen added to a stirred mixture of H₂O/ice (1/1, v/v; 80 mL, totalvolume). The product is extracted in CH₂Cl₂ (2×200 mL). The organicphase is washed with an aqueous saturated solution of Na₂CO₃ (70 mL),dried (Na₂SO₄), filtered and concentrated in vacuo. The residue ispurified by silica gel (170 g) column chromatography (CH₂Cl₂/Et₂O, 95/5,then 90/10) to afford the title compound: ES-MS: 320.1 [M+H]⁺; singlepeak at t_(R)=8.76 min (System 2); R_(f)=0.13 (CH₂Cl₂/Et₂O, 95/5).

[4-(6-Hydroxy-pyrimidin-4-ylmethyl)-phenyl]-carbamic acid tert-butylester

Raney Nickel (6.0 g, in EtOH) is added to a suspension of[4-(6-hydroxy-2-mercapto-pyrimidin-4-ylmethyl)-phenyl]-carbamic acidtert-butyl ester (2.0 g, 5.99 mmol) in MeOH (58 mL), under an argonatmosphere. The resulting mixture is heated to reflux for 2 h (oil bathis pre-heated to 90-95° C.), allowed to cool to rt, filtered through apad of celite and concentrated in vacuo. The residue is purified bysilica gel (160 g) column chromatography (CH₂Cl₂/MeOH, 95/5, then 90/10)to provide the title compound as a white solid: ES-MS: 302.1 [M+H]⁺;single peak at t_(R)=6.54 min (System 2); R_(f)=0.34 (CH₂Cl₂/MeOH,90/10).

[4-(6-Hydroxy-2-mercapto-pyrimidin-4-ylmethyl)-phenyl]-carbamic acidtert-butyl ester

A mixture of 4-(4-tert-butoxycarbonylamino-phenyl)-3-oxo-butyric acidethyl ester (10.5 g, 32.7 mmol), thiourea (2.5 g, 32.7 mmol) andpotassium tert-butoxide (8.3 g, 71.9 mmol, 2.2 equiv) in butan-1-ol (30mL) is heated to 50° C. (oil bath temperature) for 23 h, under an argonatmosphere. The resulting yellow suspension is diluted with butan-1-ol(30 mL), neutralized by addition on 1N HCl (65 mL), diluted with H₂O (20mL) and extracted with CHCl₃ (2×100 mL). The organic phase is dried(Na₂SO₄), filtered (washing the filter cake with copious amount ofCHCl₃) and concentrated in vacuo. After silica gel (300 g) columnchromatography purification (CHCl₃/MeOH, 90/10), the product is treatedwith CH₂Cl₂ (200 mL). The resulting suspension is allowed to stir at rtfor 20 min, then diluted with hexane (200 mL) and filtered through aglass sintered funnel. The white residue is washed with a mixture (120mL) of CH₂Cl₂/hexane (11, v/v) and dried in vacuo to afford the titlecompound: ES-MS: 334.0 [M+H]⁺; single peak at t_(R)=7.04 min (System 2);R_(f)=0.34 (CHCl₃/MeOH, 90/10).

4-(4-tert-Butoxycarbonylamino-phenyl)-3-oxo-butyric acid ethyl ester

A suspension of 4-(4-nitro-phenyl)-3-oxo-butyric acid ethyl ester (8.3g, 33.0 mmol), di-tert-butyl dicarbonate (14.4 g, 66.0 mmol, 2 equiv),and palladium (10%) on carbon (0.825 g) in EtOH (200 mL) and THF (50 mL)is stirred for 1 h at rt, under a hydrogen atmosphere. The reactionmixture is filtered through a pad of celite and the filtrate isconcentrated in vacuo. The residue is purified by silica gel (300 g)column chromatography (CH₂Cl₂/AcOEt, 90/10) to provide the titlecompound as a white solid: ES-MS: 320.1 [M+H]⁺; single peak att_(R)=8.76 min (System 2); R_(f)=0.54 (CH₂Cl₂/AcOEt, 90/10).

4-(4-Nitro-phenyl)-3-oxo-butyric acid ethyl ester can be preparedaccording to reported protocols [M. Ohkubo, A Kuno, H. Sakai, Y.Suglyama, H. Takasugi; Chem. Pharm. Bull. 42 (6), 1279-1285 (1994)].

Example 1181-4-(6-Chloro-pyrimidin-4-ylmethyl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea

The title compound is prepared as described in Example 117 but usingα,α,α-trifluoro-m-tolyl-isocyanate and stirring the reaction mixture for3.5 h. After chromatography purification the product is repeatedlywashed with small portions of CH₂Cl₂ and dried in vacuo to afford thetitle compound as a white solid: ES-MS: 406.9 [M+H]⁺; single peak att_(R)=8.84 min (System 2); R_(f)=0.29 (CH₂Cl₂/MeOH, 95/5).

Example 1191-[4-(6-Methylamino-pyrimidin-4-ylmethyl)-phenyl]-3-p-tolyl-urea

The title compound is prepared as described in Example 102 but using[6-(4-amino-benzyl)-pyrimidin-4-yl]-methyl-amine and stirring thereaction mixture for 6 h. The title compound is obtained as a whitesolid: ES-MS: 348.0 [M+H]⁺; single peak at t_(R)=6.67 min (System 2).

[6-(4-Amino-benzyl)-pyrimidin-4-yl]-methyl-amine

A 4 N solution of HCl in dioxane (11.7 mL, 46.9 mmol, 30 equiv) is addedto a solution of [4-(6-chloro-pyrimidin-4-ylmethyl)-phenyl]-carbamicacid tert-butyl ester (Example 117) (0.50 g, 1.56 mmol) in CH₂Cl₂ (6.7mL), under an argon atmosphere. The resulting white suspension isstirred at rt for 6.5 h. Additional 4 N HCl solution (1.1 mL, 4.6 mmol,3.0 equiv) is added. The reaction mixture is allowed to stir for 0.5 hand concentrated in vacuo to afford 0.467 g of crude4-(6-chloro-pyrimidin-4-ylmethyl)-phenylamine as a white solid. An 8 Msolution of methylamine in EtOH (5.1 mL, 40.0 mmol, 30 equiv) Is addedto a solution of crude 4-(6-chloro-pyrimidin-4-ylmethyl)phenylamine(0.300 g, 1.37 mmol) in EtOH (2.7 mL), under an argon atmosphere. Themixture Is heated to 50° C. (oil bath temperature) for 5 h, allowed tocool to rt and concentrated in vacuo. The residue is purified by silicagel (48 g) column chromatography (CH₂Cl₂/MeOH, 85/15) to afford thetitle compound as a light yellow oil: ES-MS: 215.0 [M+H]⁺; single peakat t_(R)=3.03 min (System 2); R_(f)=0.49 (CH₂Cl₂/MeOH, 85/15).

Example 1201-(4-Ethyl-phenyl)-3-[4-(6-methylamino-pyrimidin-4-ylmethyl)-phenyl]-urea

The title compound Is prepared as described in Example 102 but using[6-(4-amino-benzyl)-pyrimidin-4-yl]-methyl-amine (Example 119) and4-ethyl-phenyl-isocyanate. The reaction mixture is stirred for 6 h. Thetitle compound is obtained as a white solid: ES-MS: 362.0 [M+H]⁺; singlepeak at t_(R)=7.14 min (System 2).

Example 1211-[4-(6-methylamino-pyrimidin-4-ylmethyl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea

The title compound is prepared as described in Example 102 but using[6-(4-amino-benzyl)-pyrimidin-4-yl]-methyl-amine (Example 119) andα,α,α-trifluoro-m-tolyl-isocyanate. The reaction mixture is stirred for3 h. The title compound is obtained as a white solid: ES-MS: 402.0[M+H]⁺; single peak at t_(R)=7.34 min (System 2); R_(f)=0.32(CH₂Cl₂/MeOH, 90/10).

Example 1221-}4-[2-(1H-Tetrazol-5-yl)-pyridin-4-yloxy]-phenyl}-3-(3-trifluoromethyl-phenyl)-urea

The title compound is prepared as described in Example 102 but using4-[2-(1H-tetrazol-5-yl)-pyridin-4-yloxy]-phenylamine andα,α,α-trifluoro-m-tolyl-isocyanate. The reaction mixture is stirred for4 h. The crude product Is washed with a solution of CH₂Cl₂/MeOH (95/5)and dried In vacuo to afford the title compound as a beige solid: ES-MS:441.9 [M+H]⁺; single peak at t_(R)=7.93 min (System 2); R_(f)=0.36(CH₂Cl₂/MeOH, 80/20).

4-[2-(1H-tetrazol-5-yl)-pyridin-4-yloxy]-phenylamine

A mixture of 4-(4-amino-phenoxy)-pyridine-2-carbonitrile (Example 102)(2.6 g, 12.3 mmol), sodium azide (6.6 g, 102 mmol, 8.3 equiv), andammonium chloride in DMF abs. (180 mL) is heated to 70° C. for 7.5 h,under an argon atmosphere. The reaction mixture is allowed to cool tort, filtered through a glass sintered funnel and concentrated in vacuo.The residue is purified by silica gel (390 g) column chromatography(CH₂Cl₂/MeOH, 80/20) to afford the title compound as a beige solid:ES-MS: 255.0 [M+H]⁺; single peak at t_(R)=3.98 min (System 2);R_(f)=0.20 (CH₂Cl₂/MeOH, 75/25).

Example 1231-(4-Ethyl-phenyl)-3-{4-[2-(1H-tetrazol-5-yl)-pyridin-4-yloxy]-phenyl}-urea

The title compound is prepared as described In Example 102 but using4-[2-(1H-tetrazol-5-yl)-pyridin-4-yloxy]-phenylamine (Example 122) and4-ethyl-phenyl-isocyanate. The reaction mixture is stirred for 4 h. Thecrude product is washed with a solution of CH₂Cl₂/MeOH (95/5) and driedin vacuo to afford the title compound as a beige solid: ES-MS: 402.0[M+H]⁺; single peak at t_(R)=7.73 min (System 2); R_(f)=0.20(CH₂Cl₂/MeOH, 80/20).

Example 1241-{4-[2-(1-Methyl-1H-tetrazol-5-yl)-pyridin-4-yloxy]-phenyl}-3-(3-trifluoromethyl-phenyl)-urea

Iodomethane (0.21 mL, 3.40 mmol, 1.5 equiv) is added to a cold (0° C.)mixture of1-{4-[2-(1H-tetrazol-5yl)-pyridin-4-yloxy]-phenyl)-3-(3-trifluoromethyl-phenyl)-urea(Example 122) (1.0 g, 2.27 mmol) and potassium carbonate (0.94 g, 6.80mmol, 3.0 equiv) in DMF abs. (5.8 mL), under an argon atmosphere. Thereaction mixture is stirred at 0° C. for 2 h, allowed to warm to rt andstirred for additional 20 h. The resulting brown suspension is filteredand concentrated in vacuo. MeOH (10 mL) and DMF (0.5 mL) are added tothe residue and the resulting suspension is filtered. The white solid iswashed with MeOH and dried in vacuo to afford the title compound as awhite solid. The filtrate is concentrated in vacuo and the residue ispurified by MPLC (CH₃CN/H₂O/TFA) to afford additional title compound asa beige solid: ES-MS: 455.9 [M+H]⁺; single peak at t_(R)=9.15 min(System 2).

Example 1251-{4-[2-(2-Methyl-2H-tetrazol-5-yl)-pyridin-4-yloxy]-phenyl}-3-(3-trifluoromethyl-phenyl)-urea

The MPLC purification of the residue obtained from the concentratedfiltrate of Example 124 affords the title compound as a beige solid:ES-MS: 455.9 [M+H]⁺; single peak at t_(R)=8.24 min (System 2).

Example 1261-(4-Ethyl-phenyl)-3-{4-[2-(1-methyl-1H-tetrazol-5-yl)-pyridin-4-yloxy]-phenyl}-urea

The title compound is prepared as described in Example 124 but using1-(4-ethyl-phenyl)-3-{4-[2-(1H-tetrazol-5-yl)-pyridin-4-yloxy]-phenyl}-urea(Example 123). The crude product is purified by MPLC (CH₃CN/H₂O/TFA) toafford the title compound as a white solid: ES-MS: 416.0 [M+H]⁺; singlepeak at t_(R)=8.97 min (System 2).

Example 1271-(4-Ethyl-phenyl)-3-{4-[2-(2-methyl-2H-tetrazol-5-yl)-pyridin-4-yloxy]-phenyl}-urea

The MPLC purification of the crude product of Example 126 affords thetitle compound as a white solid: ES-MS: 416.0 [M+H]⁺; single peak att_(R)=8.06 min (System 2).

Example 128N-(4-(4-Chloropyrimidin-6-yl-oxy)-phenyl)-N′-(3-trifluoromethyl-4-(piperidin-1-ylmethyl)-phenyl)-urea

The title compound is prepared from3-trifluormethyl-4-(piperidin-1-ylmethyl)-phenylamine (Stage 128.1) and4-(6-chloro-pyrimidin-4-yl-oxy)-aniline (Stage 21.1) analogously toExample 85: MS: [M+1]⁺=505; ¹H-NMR (DMSO-d₆): 8.99 (s, 1H), 8.84 (s,1H), 8.62 (s, 1H), 7.93 (s, 1H), 7.62 (d, 1H), 7.55 (m, 1H), 7.51 (d,2H), 7.32 (s, 1H), 7.14 (d, 2H), 3.47 (s, 2H), 2.31 (sb, 4H), 1.49 (m,4H), 1.39 (m, 2H).

The starting materials are prepared as follows:

Stage 128.1: 3-Trifluormethyl-4-(piperidin-1-ylmethyl)-phenylamine

To a solution of2,2,2-trifluoro-N-(4-piperidin-1-ylmethyl-3-trifluoromethyl-phenyl)-acetamide(Stage 128.2; 1.427 g, 4.03 mmol) in boiling methanol (42 ml), 20 ml ofa 1 N solution of K₂CO₃ in water are added dropwise. After 2 h stirring,the reaction mixture is cooled to rt, concentrated in vacuo and theresidue re-dissolved in AcOEt and water. The aqueous layer is separatedoff and extracted twice with AcOEt. The organic phases are washed withwater and brine, dried (Na₂SO₄) and concentrated to yield the titlecompound: MS: [M+1]⁺=259; ¹H-NMR (DMSO-d₆): 7.28 (d, 1H), 6.82 (d, 1H),7.73 (dd, 1H), 5.40 (s, H₂N), 3.32 (s, 2H), 2.27 (sb, 4H), 1.46 (m, 4H),1.39 (m, 2H).

Stage 128.2:2,2,2-Trifluoro-N-(4-piperidin-1-ylmethyl-3-trifluoromethyl-phenyl)-acetamide

To a solution ofN-(4-bromomethyl-3-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide(Stage 128.3; 1.465 g, 4.19 mmol) in acetonitril (35 ml) underN₂-atmosphere, piperidine (1.25 ml, 12.7 mmol) is added. After 30 min atrt the reaction mixture is diluted with water and partially concentratedin vacuo. The aqueous residue Is acidified to pH 5 by addition of 0.1 NHCl and extracted 3× with AcOEt. The organic layers are washed withwater and brine, dried (Na₂SO₄) and concentrated. Column chromatography(SiO₂; hexane/AcOEt 3:2) gives the title compound: MS: [M+1]⁺=355;¹H-NMR (DMSO-d₆): 11.48 (s, HN), 8.02 (s, 1H), 7.91 (dd, 1H), 7.77 (d,1H), 3.52 (s, 2H), 2.32 (sb, 4H), 1.50 (m, 4H), 1.40 (m, 2H).

Stage 128.3: 2N-(4-Bromomethyl-3-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide

Under N₂-atmosphere, a suspension ofN-(4-methyl-3-trifluoromethyl-phenyl)2,2,2-trifluoro-acetamide (Stage128.4; 5.21 g, 19.2 mmol), N-bromosuccinimide (15 g, 84 mmol) andazo-iso-butyronitrile (740 mg, 4.5 mmol) in 430 ml of CCl₄ is heated to85° C. for 15 h. The hot mixture is filtered, the solid washed with CCl₄and discarded. The filtrate is concentrated, the residue re-dissolved inCH₂Cl₂ (0.7 L) and washed twice with 0.5 M solution of Na₂S₂O₃ andbrine. The inorganic phases are extracted with 2 portions of CH₂Cl₂, theorganic phases dried (Na₂SO₄) and concentrated. Column chromatography(SiO₂; hexane/CH₂Cl₂ 1:1) yields the title compound: ¹H-NMR (DMSO-d₆):11.59 (s, HN), 8.06 (d, 1H), 7.97 (dd, 1H), 7.76 (d, 1H), 4.77 (s, 2H).

Stage 128.4:N-(4-Methyl-3-trifluoromethyl-phenyl)-2.2.2-trifluoro-acetamide

To an ice-cooled solution of 5-amino-2-methylbenzotrifluoride (3.77 g,21.5 mmol) and pyridine (17.3 ml, 215 mmol) in 50 ml of CH₂Cl₂ underN₂-atmosphere, trifluoroacetic acid anhydride (3.3 ml, 23 mmol) is addeddropwise. After warming up to rt, the mixture is diluted with CH₂Cl₂ andwashed 3× with a 10% solution of citric acid in water. The aqueouslayers are extracted twice with CH₂Cl₂, the organic phases dried(Na₂SO₄) and concentrated. Sublimation in a Kugelrohr oven (0.1 mbar;oven at 150° C.) yields the title compound: m.p.: 72-74° C.

Example 129N-(4-(4-Chloropyrimidin-6-yl-oxy)-phenyl)-N′-(3-methoxy-4-(4-methyl-piperazin-1-ylmethyl)-phenyl)-urea

A solution of triphosgene (580 mg, 1.96 mmol) in CH₂Cl₂ (60 ml) underN₂-atmosphere is cooled by an ice bath.4-(6-Chloro-pyrimidin-4-yl-oxy)-aniline (Stage 21.1; 1.30 g, 5.86 mmol)and NEt₃ (0.82 ml, 5.86 mmol) in CH₂Cl₂ (30 ml) is added dropwise andthe suspension stirred for 15 min. Then a solution of3-methoxy-4-(4-methyl-piperazin-1-ylmethyl)-phenylamine (Stage 129.1;1.15 g, 4.89 mmol) and NEt₃ (0.68 ml, 4.89 mmol) in CH₂Cl₂ (30 ml) isadded dropwise and the mixture stirred for 30 min in the ice bath,whereby a solution is formed. After stirring for 4.5 h at rt, thereaction mixture is added to a saturated NaHCO₃ solution and extracted3× with CH₂Cl₂. The organic phases are washed with water and brine,dried (Na₂SO₄) and concentrated. Medium pressure reverse phase liquidchromatography (Nucleosil C18; water-acetonitrile gradient+TFA) yieldsafter neutralization the title compound: MS: [M+1]⁺=483; ¹H-NMR(DMSO-d₆): 8.74 & 8.69 (2s, 2HN), 8.63 (s, 1H), 7.50 (d, 2H), 7.31 (s,1H), 7.24 (s, 1H), 7.13 (m, 3H), 6.88 (d, 1H), 3.75 (s, H₃C), 3.37 (s,2H), 2.5-2.2 (m, 8H), 2.15 (s, H₃C).

The starting materials are prepared as described in Example 87:

Stage 129.1: 3-Methoxy-4-(4-methyl-piperazin-1-ylmethyl)-phenylamine

Hydrogenation of 3-methoxy-4(4-methyl-piperazin-1-ylmethyl)-nitrobenzene(Raney Nickel, THF) yields the title compound: MS: [M+1]⁺=236; ¹H-NMR(DMSO-d₆): 6.80 (d, 1H), 6.15 (s, 1H), 6.06 (d, 1H), 4.95 (s, 2H), 3.63(s, H₃C), 3.22 (s, 2H), 2.27 (sb, 8H), 2.10 )s, (H₃C).

Stage 129.2: 3-Methoxy-4(4-methyl-piperazin-1-ylmethyl)-nitrobenzene

Reduction of(4-methyl-piperazin-1-yl)-(4-nitro-2-methoxy-phenyl)methanone (DIBAH,THF, −75° C.→40° C.) yields the title compound: MS: [M+1]⁺=266; Anal.:CHN.

Stage 129.3:(4-Methyl-piperazin-1-yl)-(4-nitro-2-methoxy-phenyl)methanone

Prepared from 2-methoxy-4-nitrobenzoic acid and 1-methyl-piperazine(TPTU, CH₂Cl₂/CH₃CN, Et₃N): MS: [M+1]⁺=280; Anal.: CHN.

Example 130N-(4-(4-Azidopyrimidin-6-yl-oxy)-phenyl)-N′-(3-trifluoromethyl-4-(piperidin-1-ylmethyl)-phenyl)-urea

A mixture ofN-(4-(4-chloropyrimidin-6-yl-oxy)-phenyl)-N′-(3-trifluoromethyl-4-(piperidin-1-ylmethyl)-phenyl)-urea(Example 128; 350 mg, 0.69 mmol) and NaN₃ (91 mg, 1.4 mmol) in 7 ml ofDMF is stirred for 2 h at 70° C. The resulting mixture is concentratedin vacuo, the residue diluted with AcOEt and water, the aqueous layerseparated off and extracted twice with AcOEt. The organic phases arewashed with water and brine, dried (Na₂SO₄) and concentrated to yieldthe title compound: MS: [M+1]⁺=513.

Example 131N-(4-(4-Aminopyrimidin-6-yl-oxy)-phenyl)-N′-(3-trifluoromethyl-4-(piperidin-1-ylmethyl)-phenyl)-urea

Hydrogenation ofN-(4-(4-azidopyrimidin-6-yl-oxy)-phenyl)-N′-(3-trifluoromethyl-4-(piperidin-1-ylmethyl)-phenyl)-urea(Example 130; 213 mg, 0.41 mmol) in the presence of 10% Pd/C (40 mg) in10 ml of THF during 2 h at rt, filtration and concentration of thefiltrate affords the title compound: MS: [M+1]⁺=487; ¹H-NMR (DMSO-d₆):9.09 & 8.92 (2s, 2HN), 8.03 & 7.93 (2s, 2H), 7.69 & 7.65 (2m, 2H), 7.47& 7.03 (2d, 2×2H), 6.79 (s, 2H), 5.6 (s, 1H), 3.46 (s, 2H), 2.31 (m,4H), 1.49 (m, 4H), 1.40 (m, 2H).

Example 132N-(4-(4-Chloropyrimidin-6-yl-oxy)-phenyl)-N′-(3-trifluoromethyl-5-piperidin-1-ylmethyl)-phenyl)-urea

The title compound is prepared analogously to Example 129: MS:[M+1]⁺=506; ¹H-NMR (CD₃OD): 8.53 (s, 1H), 7.83 (s, 1H), 7.58 (s, 1H),7.54 (d, 2H), 7.30 (s, 1H), 7.14 (d, 2H), 7.09 (s, 1H), 3.57 (s, 2H),2.48 (m, 4H), 1.64 (m, 4H), 1.50 (m, 2H).

The starting materials are prepared as described in Example 87:

Stage 132.1: 3-Trifluoromethyl-5-(piperidin-1-ylmethyl)-phenylamine

Hydrogenation of 3-trifluoromethyl-5-(piperidin-1-ylmethyl)-nitrobenzene[Raney Nickel/Mo (BK 113W Degussa), THF] yields the title compound: MS:[M+1]⁺=259; ¹H-NMR (DMSO-d₆): 6.70, 6.64 & 6.62 (3d, 3H), 5.59 (s, H₂N),3.26 (s, 2H), 2.25 (m, 4H), 1.44 (m, 4H), 1.33 (m, 2H).

Stage 132.2: 3-Trifluoromethyl-5-(piperidin-1-ylmethyl)-nitrobenzene

Reduction of(piperidin-1-yl)-(3-nitro-5-trifluormethyl-phenyl)-methanone (DIBAH,THF, −25° C.) yields the title compound: MS: [M]⁻=288.

Stage 132.3:(Piperidin-1-yl)-(3-nitro-5-trifluormethyl-phenyl)-methanone

Prepared from 3-nitro-5-trifluormethyl-benzoic acid and piperidine(TPTU, CH₂Cl₂/CH₃CN, Et₃N): MS: [M+1]⁺=303; TLC R_(f)=0.27 (hexane/AcOEt7:3).

Example 133N-(4-(4-Chloropyrimidin-6-yl-oxy)-phenyl)-N′-(3-trifluoromethyl-4-(4-ethyl-piperazin-1-ylmethyl)-phenyl)-urea

The title compound is prepared analogously to Example 128: MS:[M+1]⁺=535; ¹H-NMR (DMSO-d₆): 9.00 & 8.84 (2s, 2HN), 8.69 (s, 1H), 7.92(s, 1H), 7.56 (m, 2H), 7.48 (d, 2H), 7.29 (s, 1H), 7.12 (d, 2H), 3.48(s, 2H), 2.35 (m, 10H), 0.94 (t, H₃C).

The starting materials are prepared as described in Example 128:

Stage 133.1:3-Trifluormethyl-4-(4-ethylpiperazin-1-ylmethyl)-phenylamine

Hydrolysis of2,2,2-trifluoro-N-[4-(4-ethylpiperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-acetamidegives the title compound: MS: [M+1]⁺=288; ¹H-NMR (DMSO-d₆): 7.22 (d,1H), 6.79 (d, 1H), 7.69 (dd, 1H), 5.38 (s, H₂N), 3.32 (s, 2H), 2.29 (sb,8H), 2.25 (q, 2H), 0.92 (t, H₃C).

Stage 133.2:2,2,2-Trifluoro-N-(4-(4-ethylpiperazin-1-ylmethyl)-3-trifluoromethyl-phenyl)-acetamide

Reaction ofN-(4-bromomethyl-3-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide(Stage 128.3) with N-ethylpiperazine gives the title compound: MS:[M+1]⁺=384; ¹H-NMR (CDCl₃): 8.0 (sb, HN), 7.8 (m, 3H), 3.63 (s, 2H),2.51 (sb, 8H), 2.43 (q, 2H), 1.09 (t, H₃C).

Example 134N-(4-(6-Chloropyrimidin-4-yl-oxy)-phenyl)-N′-{5-trifluoromethyl-3-[(4-ethylpiperazin-1-ylmethyl)]-phenyl}-urea

To an ice-cold solution of 4-(6-chloro-pyrimidin-4-yl-oxy)-aniline(Stage 21.1; 0.926 g, 4.18 mmol) and NEt₃ (0.64 ml, 4.6 mmol) in CH₂Cl₂(30 ml) under N₂-atmosphere, phosgene (2.32 ml of a 20% solution intoluene, 4.39 mmol) in CH₂Cl₂ (10 ml) is added dropwise. The resultingsuspension is stirred for 1 h, then filtered under exclusion of moistureand the filtrate concentrated in vacuo. THF (20 ml) and NEt₃ (0.64 ml,4.6 mmol) is then added to the residue. After cooling in an ice bath,3-(4-ethyl-piperazin-1-ylmethyl)-5-trifluoromethyl-phenylamine (1.00 g,3.48 mmol) dissolved in THF (20 ml) is added dropwise and the reactionmixture stirred for 30 min at 0° C. and 2 h at rt. Then it is dilutedwith water and AcOEt, the aqueous layer separated off and extractedtwice with AcOEt. The organic phases are washed with water and brine,dried (Na₂SO₄) and concentrated. Column chromatography (SiO₂;AcOEt/EtOH/Et₃N 90:10:2→80:20:2) and crystallization from ether affordsthe title compound: m.p.: 168-169° C.; MS: [M+1]⁺=535; ¹H-NMR (CD₃OD):8.54 (s, 1H), 7.82 (s, 1H), 7.60 (s, 1H), 7.54 (d, 2H), 7.30 (s, 1H),7.14 (d, 2H), 7.09 (s, 1H), 3.60 (s, 2H), 2.57 (m, 8H), 2.47 (q, 2H),1.12 (t, 3H).

The starting materials are prepared as follows:

Stage 134.1:3-(4-Ethyl-piperazin-1-ylmethyl)-5-trifluoromethyl-phenylamine

To a solution of(3-amino-5-trifluoromethyl-phenyl)-(4-ethyl-piperazin-1-yl)-methanone(14.6 g, 48.5 mmol) in THF (120 ml) under N₂-atmosphere, a 1 M solutionof BH₃.THF (145.5 ml) is added dropwise (exothermic). The mixture isstirred for 14 h at rt and then 5 h at 65° C. After cooling to rt, HClconc./H₂O 1:1 (250 ml) Is added and the mixture stirred for 15 h. Thesuspension is filtered, the filtrate extracted 3 times with AcOEt. Theorganic phases are washed twice with 1 N HCl and then discarded. Thecombined acidic phases are made basic by addition of saturated Na₂CO₃solution and extracted 3 times with AcOEt. The organic layers are washedtwice with water and brine, dried (Na₂SO₄) and concentrated. Columnchromatography (SiO₂; AcOEt/EtOH/NH₃ 95:5:1→90:10:1) followed byextraction between 3 portions of AcOEt, 3 portions of water and finallybrine, drying (Na₂SO₄) and concentration yields the title compound as anoil: MS: [M+1]⁺=288; ¹H-NMR (CDCl₃): 6.94 (s, 1H), 6.82 (s, 1H), 6.78(s, 1H), 3.82 (sb, H₂N), 3.46 (s, 2H), 2.51 (m, 8H), 2.44 (q, 2H), 1.10(t, 3H).

Stage 134.2:(3-Amino-5-trifluoromethyl-phenyl)-(4-ethyl-piperazin-1-yl)-methanone

Hydrogenation of(3-nitro-5-trifluoromethyl-phenyl)-(4-ethyl-piperazin-1-yl)-methanone(16.5 g, 50 mmol) in ethanol (300 ml) In the presence of Raney-Nickel (3g), filtration through celite, concentration of the filtrate andcrystallization from hexane gives the title compound: m.p.: 104° C.; MS:[M+1]⁺=302; ¹H-NMR (CDCl₃): 6.96 (s, 1H), 6.91 (s, 1H), 6.83 (s, 1H),3.99 (sb, H₂N), 3.80 (m, 2H), 3.44 (m, 2H), 2.53 (m, 2H), 2.46 (q, 2H),2.40 (m, 2H), 1.12 (t, 3H).

Stage 134.3:(3-Nitro-5-trifluoromethyl-phenyl)-(4-ethyl-piperazin-1-yl)-methanone

In an ice bath under N₂-atmosphere, 3-nitro-5-trifluoromethyl-benzoicacid (Lancaster; 11.8 g, 50 mmol), CH₂Cl₂ (150 ml), a few drops of DMFand oxalylchloride ( 7.0 ml, 81 mmol) are mixed and then stirred for 3 hat rt. The resulting solution is concentrated in vacuo. The residue isdissolved in CH₂Cl₂ (170 ml) and added dropwise to an ice cooledsolution of N-ethyl-piperazine (12.7 ml, 0.10 mol) in CH₂Cl₂ (100 ml).After stirring for 1 h at rt, the mixture is washed with a dilutedsolution of Na₂CO₃, 2 portions of water and finally brine. The aqueouslayers are re-extracted twice with AcOEt, the combined organic phasesdried (Na₂SO₄) and concentrated giving the title compound as an oil: MS:[M+1]⁺=332; ¹H-NMR (CDCl₃): 8.53 (s, 1H), 8.44 (s, 1H), 8.00 (s, 1H),3.84 (m, 2H), 3.43 (m, 2H), 2.57 (m, 2H), 2.48 (q, 2H), 2.44 (m, 2H),1.12 (t, 3H).

Example 135N-(4-(6-Chloropyrimidin-4-yl-oxy)-phenyl)-N′-[5-trifluoromethyl-3-(dimethylamino-methyl)-phenyl]-urea

A solution of 4-chloro-6-(4-isocyanato-phenoxy)-pyrimidine (Stage 135.1;594 mg; 2.40 mmol) in THF (2 ml) is mixed under a N₂-atmosphere with asolution of 3-dimethylaminomethyl-5-trifluoromethyl-phenylamine (Stage135.2; 524 mg; 2.40 mmol) in ether (10 ml). Stirring at rt affords thetitle compound: MS: [M+1]⁺=466.

The starting materials are prepared as follows:

Stage 135.1: 4-Chloro-6-(4-isocyanato-phenoxy)-pyrimidine

Apparatus: 2 litre 3-neck-roundbottle flask, dropping funnel, shortVigreux column and condenser. A phosgene solution (20% in toluene, 118ml; 223 mmol) diluted with toluene (800 ml) under N₂-atmosphere iscooled to approximately −20° C. Then a solution of4-(6-chloro-pyrimidin-4-yl-oxy)-aniline (Stage 21.1; 18.52 g, 83.6 mmol)in CH₂Cl₂ (400 ml) is added dropwise. The resulting suspension is heatedto distil off approximately 400 ml of solvent. Distillation Is continued(boiling point: 110° C.), while a mixture of phosgene solution (20% intoluene, 59 ml) and toluene (500 ml) is added dropwise, followed bytoluene (250 ml). The resulting clear solution (a 250 ml) in thereaction vessel is cooled to rt, filtered and the filtrate concentratedin vacuo. Distillation of the resulting waxy crude product on theKugelrohr apparatus (0.2 mbar, 200° C.) gives the title compound as asolid: m.p.: 103° C.; MS: [M+1]⁺=302; ¹H-NMR (CDCl₃): 8.57 (s, 1H), 7.17(d, 2H), 7.10 (d, 2H), 6.95 (s, 1H).

Stage 135.2: 3-Dimethylaminomethyl-5-trifluoromethyl-phenylamine

3-Amino-N,N-dimethyl-5-trifluoromethyl-benzamide (2.0 g; 8.6 mmol)dissolved in THF (20 ml) is reduced with a 1 M solution of BH₃.THF (26ml) as described in Stage 134.1, yielding the title compound: MS:[M+1]⁺=219.

Stage 135.3: 3-Amino-N,N-dimethyl-5-trifluoromethyl-benzamide

Hydrogenation of (3-nitro-N,N-dimethyl-5-trifluoromethyl-benzamide (12.6g, 48 mmol) in THF (250 ml) in the presence of Raney-Nickel (3 g),filtration through celite, concentration of the filtrate andcrystallization from hexane gives the title compound: m.p.: 154° C.; MS:[M+1]⁺=233; ¹H-NMR (CD₃OD): 6.97 (s, 1H), 6.84 (s, 2H), 3.09 (s, 3H),2.99 (s, 3H).

Stage 135.4: (3-Nitro-N,N-dimethyl-5-trifluoromethyl-benzamide

In an ice bath under N₂-atmosphere, 3-nitro-5-trifluoromethyl-benzoicacid (Lancaster; 11.8 g, 50 mmol), CH₂Cl₂ (150 ml), 3 drops of DMF andoxalylchloride ( 7.0 ml, 81 mmol) are mixed and then stirred for 2.5 hat rt. The resulting solution is concentrated in vacuo. The residue isdissolved in CH₂Cl₂ (170 ml) and added dropwise to an ice cooledsolution of dimethylamine hydrochloride (4.5 g, 55 mmol) and NEt₃ (21ml; 0.15 mol) in CH₂Cl₂ (100 ml). After stirring for 15 h at rt, themixture is worked up as described in Stage 134.3, giving the titlecompound as an oil: MS: [M+1]⁺=263; ¹H-NMR (CDCl₃): 8.53 (s, 1H), 8.47(s, 1H), 8.03 (s, 1H), 3.18 (s, 3H), 3.04 (s, 3H).

Example 136

The following compounds of Table 11 can be prepared analogously to thedescribed procedures: TABLE 11

R1 HPLC t_(R)[min]System 3 m.p. [° C.] MS [M + 1]⁺ Anal. a)  b)

N═N⁺═N⁻ NH₂ 490  464 CHN H₂O CHN c) d)

N═N⁺═N⁻NH₂ 11.3 7.6 461 435 e) f) g)

N═N⁺═N⁻NH₂NH—CH₃ 11.4 8.0 8.4 542 516 530 h) i)

N═N⁺═N⁻NH₂  8.1 475 449 j) k) l)

N═N⁺═N⁻NH₂NH—CH₃ 9.4 6.4 6.8 490 464 478 m) n)  o)

N═N⁺═N⁻NH₂ NH—CH₃ 12.7 9.2  9.6 513 487  501  CHNF H₂O p) q) r)

N═N⁺═N⁻NH₂NH—CH₃ 10.9 8.4 8.6 542 516 530 s)

NH—CH₃ 9.0 501 t)

N═N⁺═N⁻ 187-188 u) v)

NH—CH₃NH₂ w) x)

NH—CH₃NH₂ 461 447 y) z)

NH—CH₃NH₂

Example 137(±)trans-N-(4-(4-Aminopyrimidin-6-yl-oxy)-phenyl)-N′-(2-phenyl-cyclopropyl)-urea

The title compound is prepared analogously to Examples described above:MS: [M+1]⁺=362; ¹H-NMR (DMSO-d₆): 8.52 & 8.03 (2s, 2H), 7.39 (d, 2H),7.24 (m, 2H), 7.12 (m, 3H), 6.98 (d, 2H), 6.75 (s, H₂N), 6.68 (s, 1H),5.61 (s, 1H), 2.73 (m, 1H), 1.95 (m, 1H), 1.15 (m, 2H).

Example 138N-Methyl-C-[4-(4-{4-[3-(4-piperidin-1-yl-3-trifluoromethyl-phenyl)ureido]-phenoxy}-pyrimidin-2-ylamino)-phenyl]-methanesulfonamide

A suspension of1-[4-(2-chloro-pyrimidin-4-yloxy)-phenyl]-3-(4-piperidin-1-yl-3-trifluoromethyl-phenyl)-urea(compound of Example 79; 140 mol, 0.285 mmol) and ofC-(4-amino-phenyl)-N-methyl-methanesulfonamide (855 mg, 4.27 mmol) inethanol (5 mL) is stirred in a sealed tube at 60° C. for 27 h. Afterevaporating the solvent, the reaction mixture is flash chromatographed(silica gel, 2.5×45 cm, hexane/AcOEt=1:1→1:2) to give compound ofExample 138 as a beige solid: M+H=655.8; R_(f) (Hexane/AcOEt=1:1):0.319; HPLC: 6.65 min (System 1).

Compounds of Examples 139 and 140 are synthesized in analogy to thepreparation of compound of Example 35 by urea formation between thecorresponding chloro-pyrimidinyloxy-phenylamines and the substituted3-trifuoromethyl-phenyl amines by means of triphosgene. Sturctures andanalytical data are given in Table 12. TABLE 12 Ex. Structure Analyticaldata 139

M + H = 506.9/508.9; R_(f)CH₂Cl₂/MeOH = 9:1): 0.21; HPLC: 5.31 min(System 1). 140

M + H = 420.9/422.9; R_(f)hexane/AcOEt = 1:1): 0.22; HPLC: 7.31 min(System 1).

Compounds of Examples 141-143 are synthesized analogously to thepreparation of compound of Example 138. Structures and analytical dataare given in Table 13. TABLE 13 Ex. Structure Analytical data 141

M + H = 502.0; R_(f)CH₂Cl₂/MeOH = 9:1): 0.09; HPLC: 3.98 min (System 1).142

M + H = 509.9; R_(f)hexane/AcOEt = 1:1): 0.17; HPLC: 6.37 min (System1). 143

M + H = 569.8; R_(f)hexane/AcOEt = 1:2): 0.16; HPLC: 6.86 min (System1).

Compounds of Examples 144-151 are formed by urea formation between thecorresponding anilines and 4-(4-amino-phenoxy)-pyrimidin-2-ylamine(Examples 144-146) and [6-(4-amino-phenoxy)-pyrimidin-4-yl]-methyl-amine(Examples 147-151), respectively, analogously to the preparation ofcompound of Example 35. Structures and analytical data are given inTable 14. TABLE 14 Ex. Structure Analytical data 144

M + H = 471.8; R_(f)(AcOEt/hexane = 2:1): 0.24; HPLC: 5.60 min (System1). 145

M + H = 487.9; R_(f)(CH₂Cl₂/MeOH/NH₃ =8:2:0.1): 0.20; HPLC: 3.78 min(System 1). 146

M + H = 466.9 147

148

M + H = 471.8; R_(f)(hexane/AcOEt = 2:1): 0.24; HPLC: 6.00 min (System1). 149

M + H = 415.9; R_(f)(hexane/AcOEt = 1:4): 0.23; HPLC: 5.51 min (System1); Anal.: C: 57.65% (57.55%), H: 4.21% (4.35%), N: 16.52% (16.78%). 150

M + H = 431.9; R_(f)(hexane/AcOEt = 1:4): 0.21; HPLC: 5.07 min (System1); Anal.: C: 55.73% (55.43%), H: 4.32% (4.19%), N: 15.90% (16.16%). 151

M + H = 417.9; R_(f)(hexane/AcOEt = 1:4): 0.24; HPLC: 5.53 min (System1); Anal.: C: 57.56% (57.55%), H: 4.43% (4.35%), N: 16.47% (16.78%).

6-(4-Amino-phenoxy)-pyrimidin-4-ylamine (Compound of Stage 144.1)

Compound of Stage 56.1 (2.0 g, 9.725 mmol) dissolved in acqueous NH₃(25%, 80 mL) and EtOH (60 mL) is stirred in a sealed tube at 80° C. for23 h. After evaporating the solvent under reduced pressure on a waterbath at 40° C., the residue is flash chromatographed (silica gel, 5.5×65cm; CH₂Cl₂/MeOH=9:1) to give compound of Stage 144.1 as a white solid:M+H=203.0; ¹H-NMR (400 MHz, DMSO-d₆): 8.01 (s, 1H, pyrimidinyl), 6.74(d, 9 Hz, 2H, phenyl), 6.70 (s, 2H, NH₂), 6.57 (d, 9 Hz, 2H, phenyl),5.51 (s, 1H, pyrimidinyl), 5.03 (s, 2H, NH₂); R_(f) (CH₂Cl₂/MeOH=9:1):0.37; HPLC: 3.75 min (System 1).

3-Pyridin-2-yl-5-trifluoromethyl-phenylamine (Compound of Stage 146.1)

The title compound Is synthesized via Stille coupling analogously to theprocedure of Zhang et al., Synthetic Commun. 31 (8), 1129-1139 (2001)3-amino-5-bromo-benzotrifluoride (600 mg, 2.44 mmol),2-tributylstannyl-pyridine (1.0 g, 2.69 mmol), andtetrakistriphenylphosphin palladium (282 mg, 0.245 mmol) dissolved inTHF (10 mL) is stirred under Ar at 90° C. for 7 d. After concentratingunder reduced pressure, the reaction mixture is flash chromatographed(silica gel, 2.6×46 cm, AcOEt/hexane: 1:2→2:3) to give compound of Stage146.1 as a yellow oil: M+H=239.1; ¹H-NMR (400 MHz, DMSO-d₆): 8.64 (d,5.0 Hz, 1H), 7.82 (m, 2H), 7.54/7.45 (s/s, 1H/1H), 7.36 (m, 1H9, 6.90(s, 1H), 5.73 (s/broad, 2H); HPLC: 3.49 min (System 1); R_(f)(hexane/AcOEt=2:1): 1.5.

[6-(4-Amino-phenoxy)-pyrimidin-4yl]-methyl-amine (Compound of Stage148.1)

Compound of Stage 148.2 (1.28 g, 5.2 mmol) dissolved in MeOH/THF (45mL/15 mL) is hydrogenated (1 atm) in the presence of Raney-Ni during 8h. After evaporating the solvent under reduced pressure, the residue isflash chromatographed (silica gel, 5.5×60 cm; AcOEt/hexane=1:1) to givecompound of Stage 148.1 as a beige solid: M+H=217.0; ¹H-NMR (400 MHz,DMSO-d₆): 8.04 (s, 1H, NH), 6.93 (s/broad, 1H, pyriminidyl), 6.75 (d,9.0 Hz, 2H, phenyl), 6.53 (d, 9.0 Hz, 2H, phenyl), 5.85 (m/broad, 1H,pyrimidinyl), 5.03 (s, 2H, NH₂), 2.66 (s/broad, 3H, Me); R_(f)(AcOEt/hexane=1:1): 0.12; HPLC: 3.60 min (System 1).

Methyl-[4-(4-nitro-phenoxy)-pyrimidin-2-yl]-amine (Compound of Stage148.2):

Compound of Stage 148.3 (2 g, 7.95 mmol) is stirred in MeNH₂ (30% inEtOH, 40 mL) at rt for 50 min. After evaporating the solvent underreduced pressure, the residue is flash chromatographed (silica gel,5.5×60 cm; AcOEt/hexane=1:1) to give compound of Stage 148.2 as a whitesolid: M+H=247.1; R_(f) (AcOEt/hexane=1:1): 0.23; HPLC: 3.60 min (System1).

2-Chloro4-(4-nitro-phenoxy)-pyrimidine (Compound of Stage 148.3)

The title compound is synthesized analogously to the preparationcompound of Stage 22.5: M+H=252.0/253.8; HPLC: 5.97 min (System 1);¹H-NMR (400 MHz, DMSO-d₆): 8.67 (d, 5.5 Hz, 1H, pyriminidyl), 8.35 (d,9.0 Hz, 2H, phenyl), 7.55 (d, 9.0 Hz, 2H, phenyl), 76.32 d, 5.5 Hz, 1H,pyrimidinyl).

4-Methoxy-3-trifluoromethyl-phenylamine (Compound of Stage 149.1)

The title compound is prepared from1-methoxy-4-nitro-2-trifluoromethyl-benzene (1 g, 4.43 mmol) byhydrogenation (5→1.4 bar) in the presence of Raney-Ni (0.3 g) in MeOH(20 mL) during 15 h. The product is isolated by filtration of thereaction suspension over Hyflo and evaporation of the solvent underreduced pressure to give compound of Stage 149.1 as a beige solid:M+H=191.9; R_(f) (AcOEt/hexane=1:1): 0.33.

Example 1521-{4-[6-(4-Methoxy-phenylamino)-pyrimidin-4-yloxyl-phenyl}-3-[4-(2-methyl-imidazol-1-yl)-3-trifluoromethyl-phenyl-urea

The title compound is synthesized analogously to the preparation ofcompound of Example 47 by urea formation with[6-(4-amino-phenoxy)-pyrimidin-4-yl]-(4-methoxy-phenyl)-amine (Stage47.1) and 4-(2-methyl-imidazol-1-yl)-3-trifluoromethyl-phenylamine(Stage 152.1): M+H=575.8; HPLC: 4.73 min (System 1); R_(f)(AcOEt/hexane=1:1): 0.33; ¹H-NMR (400 MHz, DMSO-d₆): 9.33 (s, 1H), 9.29(s, 1H), 8.94 (s, 1H), 8.24 (s, 1H), 8.14 (s, 1H), 7.71 (d, 9.0 Hz, 1H,phenyl-CF₃), 7.52 (d, 8.5 Hz, 2H), 7.44 (d, 9.0 Hz, 1H, phenyl-CF₃),7.39 (d, 8.5 Hz, 2H), 7.13 (s, 1H), 7.11 (d, 8.5 Hz, 2H), 6.86 (d, 8.5Hz, 2H), 5.94 (s, 1H, pyrmidinyl), 3.71 (s, 3H, CH₃—O), 2.04 (s, 3H,CH₃-imidazolyl).

4-(2-Methyl-imidazol-1-yl)-3-trifluoromethyl-phenylamine (Compound ofStage 152.1)

The title compound is generated from2-methyl-1-(4-nitro-2-trifluoromethyl-phenyl)-1H-imidazole (Stage 152.2)by hydrogenation in the presence of Raney-Ni in MeOH during 14 h at rt:R_(f) (MeOH/CH₂Cl₂=1:5): 0.42; M+H=242.0; m.p.=217-219° C.

2-Methyl-1-(4-nitro-2-trifluoromethyl-phenyl)-1H-imidazole (Compound ofStage 152.2):

The title compound is prepared by hearing1-bromo-4-nitro-2-trifluoromethyl-benzene and 2-methyl-imidazole between100-150° C. during 15 h: M+H=272.0; R_(f) (MeOH/CH₂Cl₂=1:5): 0.60.

In accordance with the methods described hereinbefore, the followingcompounds [Examples 153a)-153x)], with the substituents given in Table15, are prepared: TABLE 15

Example 153 R1 R2 a)

b)

c)

d)

e)

f)

g)

h)

i)

j)

k)

l)

m)

n)

o)

4-Ethyl p)

4-Ethyl q)

4-(Isopropyl) r)

4-(Isopropyl) s)

t)

u)

H v)

H w)

x)

In accordance with the methods described hereinbefore, the followingcompounds [Examples 154a)-154e)], with the substituents given in Table16, are prepared: TABLE 16 Example 154 Structure a)

b)

c)

d)

e)

Example 155N-(6-{4-[3-(3-Trifluoromethyl-phenyl)-ureido]-phenoxy}-pyrimidin-4-yl)-acetamide

1-[4-(6-Chloro-pyrimidin-4-yloxy)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea(compound of Example 56) (100 mg, 0.245 mmol)₁ acetamide (40 mg₁ 0.678mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-xanthrene (9 mg), andtris(dibenzylideneacetone)dipalladium (6 mg) dissolved in dioxane (3 mL)are stirred at 55° C. under Ar for 8 h. After evaporating the solventunder reduced pressure, the residue is partitioned between H₂O (60 mL)and AcOEt (200 mL). The organic phase is separated, dried (MgSO₄) andconcentrated under reduced pressure. The product is purified bypreparative thin layer chromatography (four 20×20 cm silica gel plates,acetone/CH₂Cl₂=3:7): M+H=431.9; R_(f) (acetone/CH₂Cl₂=3:7): 0.29; ¹H-NMR(400 MHz, DMSO-d₆): 10.85 (s, 1H, pyrimidinyl), 9.03/8.84 (s/s, 1H/1H,urea), 8.45 (s, 1H, NH), 7.98 (s, 1H, pyrimidinyl), 7.56 (d, 8.5 Hz, 1H,phenyl-CF₃), 7.50 (d/s, 9.0 Hz, 2H/1H, phenyl/phenyl-CF₃), 7.49 (t, 1H,phenyl-CF₃), 7.29 (d, 8.5 Hz, 1H, phenyl-CF₃), 7.06 (d, 9.0 Hz, 2H,phenyl), 7.39 (d, 8.5 Hz, 2H), 7.13 (s, 1H), 7.11 (d, 8.5 Hz, 2H), 6.86(d, 8.5 Hz, 2H), 5.94 (s, 1H, pyrimidinyl), 2.09 (s, 3H, CH₃).

Example 1561-[3-Methyl-4-(6-methylamino-pyrimidin-4-yloxy)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea

[6-(4-Amino-2-methyl-phenoxy)-pyrimidin-4-yl]-methyl-amine (73 mg, 0.31mmol), 3-trifluoromethyl-phenyl-isocyanate (118 mg, 0.63 mmol), NEt₃(63.5 mg, 0.63 mmol) dissolved in CH₂Cl₂ (7 mL) are stirred at rt for1.5 h. The precipitating product is filtered off and dried in vacuo:M+H=431.9; R_(f) (hexane/AcOEt=1:1): 0.43; HPLC (System 1): 5.26 min;¹H-NMR (400 MHz, DMSO-d₆): 10.85 (s, 1H, pyrimidinyl), 9.23/8.92 (s/s,1H/1H, urea), 8.07 (s/broad, 1H, NH), 7.98 (s, 1H, pyrimidinyl), 7.56(d, 8.5 Hz, 1H, phenyl-CF₃), 7.50 (d, 9.0 Hz, 1H, phenyl-CF₃), 7.49 (t,9.0 Hz, 1H, phenyl-CF₃), 7.39 (s, 1H), 7.36 (m, 3H), 6.95 (d, 9.0 Hz,1H), phenyl-CF₃), 7.13 (s, 1H), 5.66 (s/broad, 1H, pyrimidinyl), 2.74(s/broad, 3H, CH₃NH), 2.04 (s, 3H, CH₃).

[6-(4-Amino-2-methyl-phenoxy)-pyrimidin-4-yl]-methyl-amine (Compound ofStage 156.1)

The title compound is prepared from[3-methyl-4-(6-methylamino-pyrimidin-4-yloxy)-phenyl]-carbamic acidbenzyl ester by hydrogenation in the presence of Pd/C in MeOH/THF:M+H=230.9; R_(f) (acetone/CH₂Cl₂=1:1): 0.20.

[3-Methyl-4-(6-methylamino-pyrimidin-4-yloxy)-phenyl]-carbamic acidbenzyl ester (Compound of Stage 156.2)

The title compound is prepared from[4-(6-chloro-pyrimidin-4-yloxy)-3-methyl-phenyl]-carbamic acid benzylester by aminomethylation (30% CH₃NH₂ in EtOH, 60 min, rt): M+H=363.9;R_(f) (acetone/CH₂Cl₂=3:7): 0.26.

[4-(6-Chloro-pyrimidin-4-yloxy)-3-methyl-phenyl]-carbamic acid benzylester (Compound of Stage 156.3)

(4-Hydroxy-3-methyl-phenyl)-carbamic acid benzyl ester (278 mg, 1.08mmol) and NaH (29 mg, 1.2 mmol) dissolved in DMF (5 mL) are stirred atrt for 15 min. 4,6-Dichloro-pyrimidine (177 mg, 1.19 mmol) dissolved inDMF (5 mL) is added and the reaction solution is stirred for 1 h,concentrated under reduced pressure and flash chromatographed (silicagel, 2.5×60 cm, AcOEt/hexane=1:6): M+H=370.8; R_(f) (AcOEt/hexane=1:6):0.31.

(4-Hydroxy-3-methyl-phenyl)-carbamic acid benzyl ester (Compound ofStage 156.4)

4-Amino-2-methyl-phenol (717 mg, 5.8 mmol) and benzyloxycarbonylchloride (1.09 g, 6.4 mmol) are stirred in a suspension ofAcOEt/concentrated Na₂CO₃ solution (50 mL/50 mL) for 7 h. The organicphase is concentrated under reduced pressure and flash chromatographed(silica gel, 3.8×66 cm, AcOEt/hexane=1:3): M+H=257.9; HPLC (System 1):5.43 min.

Example 1571-[4-(6-Amino-pyrimidin-4-ylmethyl)-phenyl]-3-(4-ethyl-phenyl)-urea

The title compound is prepared as described in Example 102 but using6-(4-aminobenzyl)-pyrimidin-4-ylamine, 4-ethyl-phenyl-isocyanate, andDMF as the solvent. The reaction mixture is stirred for 2 h. The titlecompound is obtained as a white solid: ES-MS: 348.0 [M+H]⁺; single peakat t_(R)=6.94 min (System 2).

6-(4-Aminobenzyl)-pyrimidin-4-ylamine

A 4 N solution of HCl in dioxane (19.2 mL, 76.4 mmol, 30 equiv) is addedto a solution of [4-(6-amino-pyrimidin-4-ylmethyl)-phenyl]-carbamic acidtert-butyl ester (770 mg, 2.56 mmol) in CH₂Cl₂ (23 mL), under an argonatmosphere. The resulting white suspension is stirred at rt for 1.5 hand concentrated in vacuo. To the residue is added a 2 M methanolicsolution of ammonia (3.8 mL, 7.68 mmol, 3 equiv) and the resultingyellow solution is concentrated in vacuo. The crude product is purifiedby silica gel (90 g) column chromatography CH₂Cl₂/MeOH, 90/10, then80/20). The title compound is obtained as a white solid: ES-MS: 201.0[M+H]⁺; single peak at t_(R)=2.00 min (System 2); R_(f)=0.20(CH₂Cl₂/MeOH, 90/10).

[4-(6-Amino-pyrimidin-4-ylmethyl)-phenyl]-carbamic acid tert-butyl ester

A suspension of [4-(6-azido-pyrimidin-4-ylmethyl)-phenyl]-carbamic acidtert-butyl ester (870 mg, 2.66 mmol) and 10% Pd/C (174 mg) in MeOH (35mL) is stirred for 1.5 h at rt and a hydrogen atmosphere. The reactionmixture is filtered through a plug of celite (washing the filter cakewith copious amounts of MeOH). The filtrate is concentrated in vacuo toafford the title compound as a beige solid: ES-MS: 301.1 [M+H]⁺; singlepeak at t_(R)=6.25 min (System 2).

[4-(6-Azido-pyrimidin-4-ylmethyl)-phenyl]-carbamic acid tert-butyl ester

A suspension of [4-(6-chloro-pyrimidin-4-ylmethyl)-phenyl]-carbamic acidtert-butyl ester (see Example 117) (1.1 g, 3.44 mmol) and sodium azide(0.31 g, 4.81 mmol, 1.4 equiv) in DMF (13 mL) is heated to 80° C. for2.5 h. The reaction mixture is allowed to cool to rt and concentrated invacuo. The residue is diluted with EtOAc (25 mL) and H₂O (66 mL). Thelayers are separated and the aqueous layer is extracted with EtOAc (2×40mL and 2×50 mL). The organic phase is dried (Na₂SO₄), filtered andconcentrated. The residue is purified by silica gel (80 g) columnchromatography CH₂Cl₂/Et₂O, 90/10). The title compound is obtained as awhite solid: ES-MS: 327.0 [M+H]⁺; single peak at t_(R)=7.42 min (System2); R_(f)=0.26 (CH₂Cl₂/Et₂O, 90/10).

Example 158 1-[4-(6-Amino-pyrimidin-4-ylmethyl)-phenyl]-3-p-tolyl-urea

The title compound is prepared as described in Example 102 but using6-(4-aminobenzyl)-pyrimidin-4-ylamine (see Example 157), and DMF as thesolvent. The reaction mixture is stirred for 3 h. The title compound isobtained as a white solid: ES-MS: 348.0 [M+H]⁺; single peak att_(R)=6.94 min (System 2).

Example 1591-[4-(6-Amino-pyrimidin-4-ylmethyl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea

The title compound is prepared as described in Example 102 but using6-(4-aminobenzyl)-pyrimidin-4-ylamine (see Example 157),α,α,α-trifluoro-m-tolyl-isocyanate, and DMF as the solvent. The reactionmixture is stirred for 4 h. The crude product is washed with aCH₂Cl₂/MeOH (99/1) solution. The title compound is obtained as a whitesolid: ES-MS: 387.9 [M+H]⁺; single peak at t_(R)=7.12 min (System 2);R_(f)=0.23 (CH₂Cl₂/MeOH, 90/10).

Example 1601-[4-(6-Amino-pyrimidin-4-ylmethyl)-phenyl]-3-(4-chloro-3-trifluoromethyl-phenyl)-urea

The title compound is prepared as described in Example 102 but using6-(4-aminobenzyl)-pyrimidin-4-ylamine (see Example 157),4-chloro-3-(trifluoromethyl)-phenyl isocyanate, and DMF as the solvent.The reaction mixture is stirred for 2 h. The title compound is obtainedas a white solid: ES-MS: 422.8 [M+H]⁺; single peak at t_(R)=7.58 min(System 2).

Example 1611-[4-(6-Amino-pyrimidin-4-ylmethyl)-phenyl]-3-(4-tert-butyl-phenyl)-urea

The title compound is prepared as described in Example 102 but using6-(4-aminobenzyl)-pyrimidin-4-ylamine (see Example 157),4-tert-butyl-phenyl-isocyanate, and DMF as the solvent. The reactionmixture is stirred for 3 h. The title compound is obtained as a whitesolid: ES-MS: 348.0 [M+H]⁺; single peak at t_(R)=6.94 min (System 2).

Example 1621-(4-{2-[2-(3-Dimethylamino-propyl)-2H-tetrazol-5-yl]-pyridin-4-yloxy}-phenyl]-3-(3-trifluoromethyl-phenyl)-urea

The title compound is prepared according to a procedure similar to thatdescribed in Example 125.

Example 1635-(6-Chloro-pyrimidin-4-yloxy)-2,3-dihydro-indole-1-carboxylic acid(3-trifluoromethyl-phenyl)-amide

To a solution of 5-(6-chloro-pyrimidinyloxy)-1H-indole (Stage 163.1;14.5 mmol) in acidic acid (80 ml), NaBH₃CN (90%; 5.06 g, 72.5 mmol) isadded portionwise. After 45 min, ice (20 g) Is added and the mixturepartially concentrated on the rotation evaporator. Then a 1 N solutionof NaOH is added to the residue (pH=11), which then is diluted withwater and AcOEt. The aqueous layer is separated off and extracted twicewith AcOEt. The organic phases are washed with 2 portions of water andbrine, dried (Na₂SO₄) and concentrated to give crude5-(6-chloro-pyrimidin-4-yloxy)2,3-dihydro-1H-indole: MS: [M+1]⁺=248.This crude 2,3-dihydro-1H-indole is then dissolved in THF (70 ml) and3-trifluoromethyl-isocyanate (93%; 3.0 g, 14.9 mmol) is added. After 16h at rt, the mixture is diluted with AcOEt and washed twice with water.The aqueous layer is extracted twice with AcOEt, the organic phaseswashed with brine, dried (Na₂SO₄) and concentrated. Columnchromatography (SiO₂; hexane/AcOEt 3:1→2:1→1:1) gives the titlecompound: m.p.: 181° C.; MS: [M+1]⁺=435; ¹H-NMR (DMSO-d₆): 8.85 (s, HN),8.62 (s, 1H), 8.00 (s, 1H), 7.88 (d, 1H), 7.84 (d, 1H), 7.50 (t, 1H),7.33 (d, 1H), 7.29 (s, 1H), 7.09 (s, 1H), 6.98 (d, 1H), 4.19 (t, 2H),3.20 (t, 2H).

The starting materials are prepared as follows:

Stage 163.1: 5-(6-Chloro-pyrimidin-4-yloxy)-1H-indole

To a mixture of NaOH (720 mg, 18 mmol) and acetone/water 1:1 (72 ml),4,6-dichloropyrimidine (2.4 g, 18 mmol) and 5-hydroxy-indole (2.68 g, 18mmol) are added. After stirring for 70 min at 65° C., the brownishsolution is cooled to rt and diluted with AcOEt and water. The aqueouslayer is separated off and extracted twice with AcOEt. The organiclayers are washed with water, saturated Na₂CO₃ solution, water andbrine, dried (Na₂SO₄) and concentrated. The crude product can be usedwithout further purification: m.p.: 137-138° C.; MS: [M+1]⁺=246.

Examples 164a)-c)

Starting from5-(6-chloro-pyrimidin-4-yloxy)-2,3-dihydro-indole-1-carboxylic acid(3-trifluoromethyl-phenyl)amide (Example 163), the following derivativesare made analogously:

-   -   a):        5-(6-azido-pyrimidin-4-yloxy)-2,3-dihydro-indole-1-carboxylic        acid (3-trifluoromethyl-phenyl)-amide;    -   b):        5-(6-amino-pyrimidin-4-yloxy)-2,3-dihydro-indole-1-carboxylic        acid (3-trifluoromethyl-phenyl)amide; and    -   c):        5-(6-methylamino-pyrimidin-4-yloxy)-2,3-dihydro-indole-1-carboxylic        acid (3-trifluoromethyl-phenyl)amide.

Example 165 Pharmacokinetic Data

The compound of formula I or I* to be tested is formulated foradministration to female MAG mice from BRL, Fuellinsdorf, Switzerland,by dissolving In DMSO/Tween 80 (90:10 v/v). The solution is diluted 1:20with distilled water and briefly sonicated to give a macroscopicallyhomogenous suspension in 5% v/v DMSO/0.5% v/v Tween 80. Finalconcentrations of compound are 10, 3 and 1 mg/ml for dosed of 50 mg/kg,respectively. Each formulation is examined under a phase contrastmicroscope and particle form described and size are estimated.

The formulated compound is administered by gavage to provide dosages of50 mg/kg. At the alloted time points mice (4 at each time) areanesthesized with 3% isoflurane in oxygen and heart blood is removedinto heparinized tubes (ca. 30 IU/mi). The animals are subsequentlykilled without recovering from the anesthetic. Plasma Is prepared fromthe blood by centrifugation (10,000 g, 5 min) and either analysedimmediately or stored frozen at −70° C. The plasma samples are mixedwith an equal volume of acetonitrile and allowed to stand at rt for20-30 min. The protein precipitate is removed by centrifugation(10,000×g) and a sample of the supernatant is analysed by reversed-phaseHPLC on Merck-Hitachi LaChrom® equipment. The sample (100 μl) isinjected onto a Nucleosil® 100-5 C18 column (Macherey & Nagel, Düren, F.R. G.) (125×4 mm) with a guard column (8×4 mm) of the same material. Thecolumn is equilibrated e.g. with a 5% v/v acetonitrile in watercontaining 0.05% trifluoroacetic acid (TFA). The sample is eluted e.g.with a gradient of 5% v/v acetonitrile to 95% v/v acetonitrile (in waterwith 0.05% v/v TFA) over a period of 10 min. The column is then preparedfor the next sample by holding the gradient at the final conditions for5 min, then returning to the starting conditions and reequilibrating for5 min. The compound is detected by absorbance, e.g. at 320 nm. Theidentity of the peak can be confirmed by retention time and UVabsorption spectrum (diode array detector 205-400 nm) compared tocontrols. The amount of compound is quantified by the external standardmethod. A calibration curve is constructed with known amounts ofcompound in plasma which is processed as described above.

Compounds of the formula I or I* according to the invention here showplasma concentrations in the area of e.g. 1 to 50 μM.

Example 166 In vitro Inhibition Data

Enzymatic (c-Abl, KDR, Flt3) data are given on Table 17 (% inhibition at10 μM). (Measurements are made as described above in the generaldescription). TABLE 17 Enzymatic data c-Abl KDR trans Flt3 Example (% at10 μM) (% at 10 μM) (% at 10 μM) 1 62 100 — 2 84 99 — 3 58 25 — 4 59 9998 5 46 99 64 6 75 100 87 7 47 97 67 8 48 78 57 9 100 92 90 10 98 100100 11 95 100 100 12 33 97 92 13 36 98 95 14 26 97 89 15 71 99 96 16 6699 94 17 18 96 92 18 61 99 88 19 92 86 63 20 84 93 69 21 70 100 94 30100 98 100 32 98 96 100

Example 7 Tablets Comprising Compounds of the Formula I or I*

Tables, comprising, as active ingredient, 100 mg of any one of thecompounds of formula I or I* of Examples 1 to 164c) are prepared withthe following composition, following standard procedures:

Composition Active Ingredient 100 mg  crystalline lactose 240 mg  Avicel80 mg PVPPXL 20 mg Aerosil  2 mg magnesium stearate  5 mg 447 mg 

Manufacture: The active ingredient is mixed with the carrier materialsand compressed by means of a tabletting machine (Korsch EKO,Stempeldurchmesser 10 mm).

Avicel is microcrystalline cellulose (FMC, Philadelphia, USA).

PVPPXL is polyvinylpolypyrrolidone, cross-linked (BASF, Germany).

Aerosil is silcium dioxide (Degussa, Germany).

Example 168 Capsules

Capsules, comprising, as active ingredient, 100 mg of any one of thecompounds of formula I or I* given in Examples 1 to 164c), of thefollowing composition are prepared accoding to standard procedures:

Composition Active Ingredient 100 mg  Avicel 200 mg  PVPPXL 15 mgAerosil  2 mg magnesium stearate 1.5 mg  318.5 mg  

Manufacturing is done by mixing the components and filling them intohard gelatine capsules, size 1.

1. A method for treating a protein kinase disease comprisingadministering a therapeutically effective amount of a diaryl ureaderivative of the formula I

wherein G is either not present, lower alkylene or C₃-C₅cycloalkyleneand Z is a radical of the formula Ia

or G is not present and Z is a radical of the formula Ib

A is CH, N or N→O and A′ is N or N→O, with the proviso that not morethan one of A and A′ can be N→O; n is 1 or 2; m is 0, 1 or 2; p is 0, 2or 3; r is 0 to 5; X is NR if p is 0, wherein R is hydrogen or anorganic moiety, or if p is 2 or 3, X is nitrogen which together with(CH₂)_(p) and the bonds represented in dotted (interrupted) lines(including the atoms to which they are bound) forms a ring, or X is CHKwherein K is lower alkyl or hydrogen and p is zero, with the provisothat the bonds represented in dotted lines, if p is zero, are absent; Y₁is O, S or CH₂; Y₂ is O, S or NH; with the proviso that(Y₁)_(n)—(Y₂)_(m) does not include O—O, S—S, NH—O, NH—S or S—O groups;each of R₁, R₂, R₃ and R₅, independently of the others, is hydrogen oran inorganic or organic moiety or any two of them together form a loweralkylene-dioxy bridge bound via the oxygen atoms, and the remaining oneof these moieties is hydrogen or an inorganic or organic moiety; and R₄(if present, that is, if r is not zero) is an inorganic or organicmoiety; or a tautomer thereof; or a pharmaceutically acceptable saltthereof;
 2. The method according to claim 1 wherein the diary ureaderivative is a compound of the formula I according to claim 1 wherein Gis either not present, lower alkylene, especially methylene or ethylene,or C₃-C₅cycloalkylene, especially cyclopropylene, and Z is a radical ofthe formula Ia according to claim 1, or G is not present and Z is aradical of the formula Ib according to claim 1; A is CH or N and A′ is Nor N→O; n is 1; m is 0 or 1; p is 0, 2 or 3; r is 0 or 1; X is NR if pis 0, wherein R is hydrogen or lower alkyl, or if p is 2 or 3, X isnitrogen which together with (CH₂)_(p) and the bonds represented indotted (interrupted) lines (including the atoms to which they are bound)forms a ring, or X is CHK wherein K is hydrogen and p is zero, with theproviso that the bonds represented in dotted lines, if p is zero, areabsent; Y₁ is O, S or CH₂; Y₂ is O; with the proviso that(Y₁)_(n)—(Y₂)_(m) does not include O—O, or S—O groups; each of R₁, R₂and R₃, independently of the others, is hydrogen, lower alkyl,especially methyl, ethyl, n-propyl, isopropyl or tert-butyl, loweralkenyl, especially isopropenyl, hydroxy-lower alkyl, especiallyhydroxy-propyl, lower alkoxy, especially methoxy, halo, especiallychloro or bromo, halo-lower alkyl, especially trifluoromethyl,halo-lower alkoxy, especially trifluoromethoxy or trifluoroethoxy,amino-lower alkyl, especially aminomethyl, amino-lower alkoxy,especially aminoethoxy, di-lower alkyl-amino, especially diethylamino,hydroxy-lower alkyl-amino, especially hydroxy-propylamino, bis-(loweralkoxy-lower alkyl)-amino, especially bis-(2-methoxy-ethyl)-amino,di-lower alkyl-amino-lower alkyl, especially dimethylaminomethyl,phenyl, morpholinyl, especially morpholin-4-yl, piperidyl, especiallypiperidin-1-yl, piperidyl-lower alkyl, especially piperidin-1-ylmethyl,lower alkyl-piperazinyl, especially 4-methyl-piperazin-1-yl or4-ethyl-piperazin-1-yl, lower alkyl-piperazinyl-lower alkyl, especially4-methyl-piperazin-1-ylmethyl or 4-ethyl-piperazin-1-ylmethyl, pyridyl,especially pyridin-2-yl, or lower alkyl-imidazolyl, especially 2- or4-methyl-imidazol-1-yl; if r is 1, R₄ is lower alkyl, especially methyl,ethyl or ispropyl, hydroxy, aminocarbonyl, lower alkyl-carbonyl,especially methylcarbonyl, cyclohexyl, halo, especially chloro orfluoro, halo-lower alkyl, especially trifluoromethyl, lower alkoxy,especially methoxy, amino, lower alkyl-amino, especially methylamino,ethylamino, isopropylamino or tert-butylamino, di-lower alkyl-amino,especially dimethylamino, lower alkenyl-amino, especiallyprop-2-enylamino or but-3-enylamino, lower alkyl-carbonyl-amino,especially methylcarbonylamino, cyano, azido, hydroxy-phenyl-amino,especially 3- or 4-hydroxy-phenyl-amino, mono or tri-loweralkoxy-phenyl-amino, especially methoxy-phenyl-amino ortrimethoxy-phenyl-amino, lower alkoxy-halo-phenyl-amino, especiallymethoxy-fluoro-phenyl-amino, phenyl-lower alkylamino, especiallybenzylamino, (mono or di-lower alkoxy)-phenyl-lower alkylamino,especially methoxy-benzylamino or dimethoxy-benzylamino,aminosulfonyl-phenyl-lower alkylamino, especiallyaminosulfonyl-benzylamino, amino-lower alkoxy-phenyl-amino, especiallyaminoethoxy-phenyl-amino, lower alkyl-amino-sulfonyl-loweralkyl-phenylamino, especially methylamino-sulfonylmethyl-phenylamino,lower alkyl-piperazinyl-lower alkylamino, especially4-methylpiperazin-1-yl-propylamino, morpholinyl-lower alkylamino,especially morpholin-4-yl-propylamino, lower alkyl-piperidyl-amino,especially 1-methyl-piperidin-4-ylamino, tetrazolyl, especially1H-tetrazol-5-yl, lower alkyl-tetrazolyl, especially loweralkyl-tetrazol-5-yl such as 1-methyl-1H-tetrazol-5-yl or2-methyl-2H-tetrazol-5-yl, or (di-lower alkyl)-amino-loweralkyl-tetrazolyl, especially (di-lower alkyl)-amino-loweralkyl-tetrazol-5-yl such as 2-(3-dimethylaminopropyl)-2H-tetrazol-5-yl;R₅ is most preferably hydrogen, or lower alkyl, especially methyl, orhalo, especially chloro; or a tautomer thereof; or a pharmaceuticallyacceptable salt thereof.
 3. The method according to claim 1 wherein thediaryl urea derivative is a compound of the formula I according to claim1 wherein A and A′ are both N, n is 1, m is 0, p is 0 or 2, r is 1, X isNH if p is 0, or if p is 2, X is nitrogen which together with (CH₂)₂ andthe bonds represented in dotted (interrupted) lines (including the atomsto which they are bound) forms a ring, Y₁ is O, G is not present, Z is aradical of the formula la according to claim 1, at least one of R₁, R₂and R₃ is a basic organic moiety, R₄ is amino or lower alkylamino and R₅is hydrogen.
 4. The method according to claim 1 wherein the diaryl ureaderivative is a compound of the formula I*

wherein A, A′, n, m, p, r, X, Y₁, Y₂ and R₁—R₅ have the meanings asdefined for a compound of formula I according to claim 1; or a tautomerthereof; or a pharmaceutically acceptable salt thereof.
 5. The methodaccording to claim 4 of a compound of the formula I* or a tautomerthereof, or a pharmaceutically acceptable salt thereof, where, in thecompound of the formula I*, A is CH, N or N→O and A′ is N or N→O, withthe proviso that not more than one of A and A′ can be N→O; n is 1; m is0; p is 0, 2 or 3; r is 0, 1 or 2; X is NR if p is 0, wherein R ishydrogen or lower alkyl, or if p is 2 or 3, X is nitrogen which togetherwith (CH₂)_(p) and the bonds represented in dotted (interrupted) lines(including the atoms to which they are bound) forms a ring, or X is CH₂and p is zero, with the proviso that the bonds represented in dottedlines, if p is zero, are absent; Y₁ is O or CH₂; each of R₁, R₂ and R₃independently of the others, is hydrogen, lower alkyl, halo, especiallybromo or chloro, halo-lower alkyl, especially trifluoromethyl, loweralkoxy, especially methoxy, halo-lower alkoxy, especially2,2,2-trifluoroethoxy, phenyl, piperidyl, especially piperidin-1-yl,piperazinyl, especially piperazin-1-yl, morpholinyl, especiallymorpholine, thiomorpholinyl, especially thiomorpholino, or any two ofthem together form a lower alkylene-dioxy bridge bound via the oxygenatoms, and the remaining one of these moieties is hydrogen or one of themoieties mentioned; if r is not zero, R₄ is lower alkyl, especiallymethyl or ethyl, lower alkoxy, especially methoxy, lower alkanoylamino,especially acetylamino, hydroxyphenylamino, especiallyp-hydroxyphenylamino, amino-lower alkyl-oxyphenyl-amino, especially4-[(2-aminoethyl)-oxyphenyl]-amino, sulfamoylphenylamino, especially4-sulfamoylphenylamino, carbamoylphenylamino, especially4-carbamoylphenylamino, [N-(hydroxy-lower alkyl)-carbamoyl]-phenylamino,especially [N-(2-hydroxyethyl)-carbamoyl]-phenylamino, halo, especiallychloro, or hydroxyl; and R₅ is hydrogen, lower alkyl or halo, especiallyhydrogen.
 6. The method according to claim 1 where the protein kinasedependent disease is a tyrosine protein kinase dependent disease,especially a proliferative disease depending on any one or more of ofthe following tyrosine protein kinases: ras, Abl, VEGF-receptor tyrosinekinase, Flt3, and/or Bcr-Abl activity.
 7. A compound of the formula Iaccording to claim 21 or a tautomer thereof, or a pharmaceuticallyacceptable salt thereof, where, in the compound of the formula I, A isCH, N or N→O and A′ is N or N→O, with the proviso that not more than oneof A and A′ can be N→O; n is 1 or 2; m is 0, 1 or 2; p is 0, 2or 3; r is1 to 5; X is NR if p is 0, wherein R is hydrogen or an organic moiety,or if p is 2 or 3, X is nitrogen which together with (CH₂)_(p) and thebonds represented in dotted (interrupted) lines (including the atoms towhich they are bound) forms a ring, with the proviso that if X is NH,each of R₄, independently of the others if r>1, is a moiety as definedin claim 1 but not bound to the rest of formula I via a —C(═O)—, —C(NR)—or —S(O₂)— bridge, or X is CHK wherein K is lower alkyl or hydrogen andp is zero, with the proviso that the bonds represented in dotted lines,if p is zero, are absent; Y₁ is O, S or CH₂; Y₂ is O, S or NH; with theproviso that (Y₁)_(n)—(Y₂)_(m) does not include O—O, S—S, NH—O, NH—S orS—O groups; each of R₁, R₂, R₃ and R₅, independently of the others, ishydrogen or an inorganic or organic moiety or any two of R₁, R₂ and R₃together form a lower alkylene-dioxy bridge bound via the oxygen atoms,and the remaining one of these moieties is hydrogen or an inorganic ororganic moiety, with the proviso that if G is not present and Z is aradical of the formula la according to claim 1, R₁, R₂ and R₃ cannot allbe hydrogen and with the further proviso that if one of R₁, R₂ and R₃ ishalo or lower alkyl-sulfonyl, the other two cannot both be hydrogen; R₄is an inorganic or organic moiety, with the proviso that if n is 1, m is0, p is 0, r is 1, X is NH, Y₁ is O, G is not present and Z is a radicalof the formula la according to claim 1, R₄, together with the benzenering containing A and A′, does not form methylpyridinyl,2-hydroxy-pyridin-4-yl or 1-H-2-oxo-1,2-dihydropyridin-4-yl.
 8. Acompound of the formula I according to claim 7 wherein G is either notpresent, lower alkylene, especially methylene or ethylene, orC₃-C₅cycloalkylene, especially cyclopropylene, and Z is a radical of theformula la according to claim 1, or G is not present and Z is a radicalof the formula Ib; A is CH or N and A′ is N or N→O; n is 1; m is 0 or 1;p is 0, 2 or 3; r is 1; X is NR if p is 0, wherein R is hydrogen orlower alkyl, or if p is 2 or 3, X is nitrogen, which together with(CH₂)_(p) and the bonds represented in dotted (interrupted) lines(including the atoms to which they are bound) forms a ring, or X is CHKwherein K is hydrogen and p is zero, with the proviso that the bondsrepresented in dotted lines, if p is zero, are absent; Y₁ is O, S orCH₂; Y₂ is O; with the proviso that (Y₁)_(n)—(Y₂)_(m) does not includeO—O, or S—O groups; each of R₁, R₂ and R₃, independently of the others,is hydrogen, lower alkyl, especially methyl, ethyl, n-propyl, isopropylor tert-butyl, lower alkenyl, especially isopropenyl, hydroxy-loweralkyl, especially hydroxy-propyl, lower alkoxy, especially methoxy,halo, especially chloro or bromo, halo-lower alkyl, especiallytrifluoromethyl, halo-lower alkoxy, especially trifluoromethoxy ortrifluoroethoxy, amino-lower alkyl, especially aminomethyl, amino-loweralkoxy, especially aminoethoxy, di-lower alkyl-amino, especiallydiethylamino, hydroxy-lower alkyl-amino, especially hydroxy-propylamino,bis-(lower alkoxy-lower alkyl)-amino, especiallybis-(2-methoxy-ethyl)-amino, di-lower alkyl-amino-lower alkyl,especially dimethylaminomethyl, phenyl, morpholinyl, especiallymorpholin-4-yl, piperidyl, especially piperidin-1-yl, piperidyl-loweralkyl, especially piperidin-1-ylmethyl, lower alkyl-piperazinyl,especially 4-methyl-piperazin-1-yl or 4-ethyl-piperazin-1-yl, loweralkyl-piperazinyl-lower alkyl, especially 4-methyl-piperazin-1-ylmethylor 4-ethyl-piperazin-1-ylmethyl, pyridyl, especially pyridin-2-yl, orlower alkyl-imidazolyl, especially 2- or 4-methyl-imidazol-1-yl, withthe proviso that if G is not present and Z is a radical of the formulaIa according to claim 1, R₁, R₂ and R₃ cannot all be hydrogen and withthe further proviso that if one of R₁, R₂ and R₃ is halo, the other twocannot both be hydrogen; R₄ is lower alkyl, especially methyl, ethyl orispropyl, hydroxy, aminocarbonyl, lower alkyl-carbonyl, especiallymethylcarbonyl, cyclohexyl, halo, especially chloro or fluoro,halo-lower alkyl, especially trifluoromethyl, lower alkoxy, especiallymethoxy, amino, lower alkyl-amino, especially methylamino, ethylamino,isopropylamino or tert-butylamino, di-lower alkyl-amino, especiallydimethylamino, lower alkenyl-amino, especially prop-2-enylamino orbut-3-enylamino, lower alkyl-carbonyl-amino, especiallymethylcarbonylamino, cyano, azido, hydroxy-phenyl-amino, especially 3-or 4-hydroxy-phenyl-amino, mono or tri-lower alkoxy-phenyl-amino,especially methoxy-phenyl-amino or trimethoxy-phenyl-amino, loweralkoxy-halo-phenyl-amino, especially methoxy-fluoro-phenyl-amino,phenyl-lower alkylamino, especially benzylamino, (mono or di-loweralkoxy)-phenyl-lower alkylamino, especially methoxy-benzylamino ordimethoxy-benzylamino, aminosulfonyl-phenyl-lower alkylamino, especiallyaminosulfonyl-benzylamino, amino-lower alkoxy-phenyl-amino, especiallyaminoethoxy-phenyl-amino, lower alkyl-amino-sulfonyl-loweralkyl-phenylamino, especially methylamino-sulfonylmethyl-phenylamino,lower alkyl-piperazinyl-lower alkylamino, especially4-methylpiperazin-1-yl-propylamino, morpholinyl-lower alkylamino,especially morpholin-4-yl-propylamino, lower alkyl-piperidyl-amino,especially 1-methyl-piperidin-4-ylamino, tetrazolyl, especially1H-tetrazol-5-yl, lower alkyl-tetrazolyl, especially loweralkyl-tetrazol-5-yl such as 1-methyl-1H-tetrazol-5-yl or2-methyl-2H-tetrazol-5-yl, or (di-lower alkyl)-amino-loweralkyl-tetrazolyl, especially (di-lower alkyl)-amino-loweralkyl-tetrazol-5-yl such as 2-(3-dimethylaminopropyl)-2H-tetrazol-5-yl,with the proviso that if X is NH, R₄ is not aminocarbonyl or loweralkyl-carbonyl and with the further proviso that if n is 1, m is 0, p is0, r is 1, X is NH, Y₁ is O, G is not present and Z is a radical of theformula Ia according to claim 1, R₄, together with the benzene ringcontaining A and A′, does not form methylpyridinyl,2-hydroxy-pyridin-4-yl or 1-H-2-oxo-1,2-dihydropyridin-4-yl; R₅ is mostpreferably hydrogen, or lower alkyl, especially methyl, or halo,especially chloro; or a tautomer thereof; or a pharmaceuticallyacceptable salt thereof.
 9. A compound of the formula I according toclaim 7 wherein A and A′ are both N, n is 1, m is 0, p is 0 or 2, r is1, X is NH if p is 0, or if p is 2, X is nitrogen which together with(CH₂)₂ and the bonds represented in dotted (interrupted) lines(including the atoms to which they are bound) forms a ring, Y, is O, Gis not present, Z is a radical of the formula Ia according to claim 1,at least one of R₁, R₂ and R₃ is a basic organic moiety, R₄ is amino orlower alkylamino and R₅ is hydrogen, or a tautomer thereof, or apharmaceutically acceptable salt thereof.
 10. A compound of the formulaI* according to claim 21 or a tautomer thereof, or a pharmaceuticallyacceptable salt thereof, where, in the compound of the formula I*, A isCH, N or N→O and A′ is N or N→O, with the proviso that not more than oneof A and A′ can be N→O; n is 1; m is 0; p is 0, 2 or 3; r is 1; X is NRif p is 0, wherein R is hydrogen or lower alkyl, or if p is 2 or 3, X isnitrogen which together with (CH₂)_(p) and the bonds represented indotted (interrupted) lines (including the atoms to which they are bound)forms a ring, or X is CH₂ and p is zero, with the proviso that the bondsrepresented in dotted lines, if p is zero, are absent; Y₁ is O or CH₂;each of R₁, R₂ and R₃ independently of the others, is hydrogen, loweralkyl, halo, especially bromo or chloro, halo-lower alkyl, especiallytrifluoromethyl, lower alkoxy, especially methoxy, halo-lower alkoxy,especially 2,2,2-trifluoroethoxy, phenyl, piperidyl, especiallypiperidin-1-yl, piperazinyl, especially piperazin-1-yl, morpholinyl,especially morpholine, thiomorpholinyl, especially thiomorpholino, orany two of them together form a lower alkylene-dioxy bridge bound viathe oxygen atoms, and the remaining one of these moieties is hydrogen orone of the moieties mentioned, with the proviso that R₁, R₂ and R₃cannot all be hydrogen and with the further proviso that if one of R₁,R₂ and R₃ is halo, the other two cannot both be hydrogen; R₄ is loweralkoxy, especially methoxy, lower alkanoylamino, especially acetylamino,hydroxyphenylamino, especially p-hydroxyphenylamino, amino-loweralkyl-oxyphenyl-amino, especially 4-[(2-aminoethyl)-oxyphenyl]-amino,sulfamoylphenylamino, especially 4-sulfamoylphenylamino,carbamoylphenylamino, especially 4-carbamoylphenylamino,[N-(hydroxy-lower alkyl)-carbamoyl]-phenylamino, especially[N-(2-hydroxyethyl)-carbamoyl]-phenylamino, or halo, especially chloro;and R₅ is hydrogen, lower alkyl or halo, especially hydrogen.
 11. Acompound of the formula I* according to claim 21 or a tautomer thereof,or a pharmaceutically acceptable salt thereof, where, in the compound ofthe formula I*, A, A′, n, m, p, Y₁, Y₂, R₁, R₂, R₃ and R₄ have themeanings given under formula I* in claim 4, and r is 1 to 5, X is NR ifp is 0, wherein R is hydrogen or an organic moiety, or if p is 2 or 3, Xis nitrogen which together with (CH₂)_(p) and the bonds represented indotted (interrupted) lines (including the atoms to which they are bound)forms a ring, or X is CH₂ and p is zero, and, if p is zero, the bondsrepresented in dotted lines are absent; with the proviso that if X isNH, each of R₄, independently of the others, if present, is a moiety asdefined in claim 4 but not bound to the rest of formula I* via a—C(═O)—, —C(NR)— or —S(O₂)— bridge, and the substituents R₁, R₂ and R₃are selected from the following moieties, whereby positions (o=ortho,m=meta, p=para) are indicated with regard to the position where the ringis bound to the rest of the molecule in formula I* (via the NH—C(═O)—X—moiety): if only R₁ is other than hydrogen: R₁=p-lower alkyl, especiallyp-methyl, p-ethyl, p-n-propyl; m-halo-lower alkyl, especiallym-trifluoromethyl; or phenyl, p-piperidin-1-yl or p-piperazin-1-yl; ifboth R₁ and R₂ are other than hydrogen: R₁=m-halo-lower alkyl,especially m-trifluoromethyl, and R₂=p-halo, especially p-bromo;R₁=m-halo-lower alkyl, especially m-trifluoromethyl, and R₂=p-halo-loweralkoxy, especially p-(2,2,2-trifluoroethoxy); R₁=m-halo-lower alkyl,especially m-trifluoromethyl, and R₂=m-lower alkoxy, especiallym-methoxy; R₁=m-halo-lower alkyl, especially m-trifluoromethyl, andR₂=p-phenyl; R₁=m-halo-lower alkyl, especially m-trifluoromethyl, andR₂=p-piperidin-1-yl or p-piperazin-1-yl; R₁=m-halo-lower alkyl,especially m-trifluoromethyl, and R₂=p-N-morpholino orp-N-thiomorpholino; R₁=m-lower alkoxy, especially m-methoxy, andR₂=p-halo, especially p-bromo (less preferred); R₁=m-lower alkoxy,especially m-methoxy, and R₂=p-halo-lower alkoxy, especiallyp-2,2,2-trifluoroethoxy; R₁=m-lower alkoxy, especially m-methoxy, andR₂=p-phenyl; or R₁=m-lower alkoxy, especially m-methoxy, andR₂=p-piperidin-1-yl or p-piperazin-1-yl; or, if R₁, R₂ and R₃ are otherthan hydrogen: R₁=m-lower alkoxy, especially m-methoxy; R₂=m-loweralkoxy, especially m-methoxy; and R₃=p-lower alkoxy, especiallyp-methoxy; or R₁=lower alkoxy, especially methoxy, and R₂ and R₃together form a lower-alkylenedioxy, especially —O—CH₂—CH₂—O—, bridge;and R₅ is hydrogen, lower alkyl or halo, especially hydrogen; with theproviso that if n is 1, m is 0, p is 0, r is 1, X is NH and Y₁ is O, R₄,together with the benzene ring containing A and A′, does not formmethylpyridinyl, 2-hydroxy-pyridin-4-yl or1-H-2-oxo-1,2-dihydropyridin-4-yl.
 12. A compound of the formula I*according to claim 21 or a tautomer thereof, or a pharmaceuticallyacceptable salt thereof, where, in the compound of the formula I*, A isCH, N or N→O and A′ is N or N→O, with the proviso that not more than oneof A and A′ can be N→O; n is 1; m is 0; p is 0, 2 or 3; r is 1 or 2; Xis NR if p is 0, wherein R is hydrogen or lower alkyl, or if p is 2 or3, X is nitrogen which together with (CH₂)_(p) and the bonds representedin dotted (interrupted) lines (including the atoms to which they arebound) forms a ring, or X is CH₂ and p is zero, with the proviso thatthe bonds represented in dotted lines, if p is zero, are absent; Y₁ is 0or CH₂; R₁, R₂ and R₃ are selected from the following moieties, wherebypositions (o=ortho, m=meta, p=para) are indicated with regard to theposition where the ring is bound to the rest of the molecule in formulaI* (via the NH—C(═O)—X-moiety): if only R₁ is other than hydrogen:R₁=p-lower alkyl, especially p-methyl, p-ethyl, p-n-propyl; m-halo-loweralkyl, especially m-trifluoromethyl; or phenyl, p-piperidin-1-yl orp-piperazin-1-yl; if both R₁ and R₂ are other than hydrogen:R₁=m-halo-lower alkyl, especially m-trifluoromethyl, and R₂=p-halo,especially p-bromo; R₁=m-halo-lower alkyl, especially m-trifluoromethyl,and R₂=p-halo-lower alkoxy, especially p-(2,2,2-trifluoroethoxy);R₁=m-halo-lower alkyl, especially m-trifluoromethyl, and R₂=m-loweralkoxy, especially m-methoxy; R₁=m-halo-lower alkyl, especiallym-trifluoromethyl, and R₂=p-phenyl; R₁=m-halo-lower alkyl, especiallym-trifluoromethyl, and R₂=p-piperidin-1-yl or p-piperazin-1-yl;R₁=m-halo-lower alkyl, especially m-trifluoromethyl, andR₂=p-N-morpholino or p-N-thiomorpholino; R₁=m-lower alkoxy, especiallym-methoxy, and R₂=p-halo, especially p-bromo (less preferred);R₁=m-lower alkoxy, especially m-methoxy, and R₂=p-halo-lower alkoxy,especially p-2,2,2-trifluoroethoxy; R₁=m-lower alkoxy, especiallym-methoxy, and R₂=p-phenyl; or R₁=m-lower alkoxy, especially m-methoxy,and R₂=p-piperidin-1-yl or p-piperazin-1-yl; or, if R₁, R₂ and R₃ areother than hydrogen: R₁=m-lower alkoxy, especially m-methoxy; R₂=m-loweralkoxy, especially m-methoxy; and R₃=p-lower alkoxy, especiallyp-methoxy; or R₁=lower alkoxy, especially methoxy, and R₂ and R₃together form a lower-alkylenedioxy, especially —O—CH₂—CH₂—O—, bridge;and, if r is not zero, R₄ is lower alkoxy, especially methoxy, loweralkanoylamino, especially acetylamino, hydroxyphenylamino, especiallyp-hydroxyphenylamino, amino-lower alkyloxyphenyl-amino, especially4-[(2-aminoethyl)-oxyphenyl]-amino, sulfamoylphenylamino, especially4-sulfamoylphenylamino, carbamoylphenylamino, especially4-carbamoylphenylamino, [N-(hydroxy-lower alkyl)-carbamoyl]-phenylamino,especially [N-(2-hydroxyethyl)-carbamoyl]-phenylamino, or halo,especially chloro; and R₅ is halo, especially chloro, lower alkyl,especially methyl, or preferably hydrogen.
 13. A compound of the formulaI* according to claim 21 selected from the group consisting ofN-(4-pyridin-4-yl-oxy-phenyl)-N′-(4-ethyl-phenyl)-urea,N-(4-pyridin-4-yl-oxy-phenyl)-N′-(3-trifluoromethyl-phenyl)-urea,N-(4-pyridin-4-yl-oxy-phenyl)-N′-(4-(2,2,2-trifluoroethoxy)-3-trifluoromethyl-phenyl)-urea;N-(4-(4-(4-hydroxyphenylamino)-pyrimidin-6-yl)-oxyphenyl)-N′-(3-trifluoromethylphenyl)-urea;andN-(4-(2-methyl-pyridin-4-yl)-oxyphenyl)-N′-(3-trifluoromethyl-phenyl)-urea;1-[4-(4-Ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-[4-(6-methylamino-pyrimidin-4-yloxy)-phenyl]-urea;or a pharmaceutically acceptable salt thereof.
 14. A compound of theformula I* according to claim 21 selected from the group consisting ofN-(4-pyridin-4-yl-oxy-phenyl)-N′-(4-n-propyl-phenyl)-urea,N-(4-pyridin-4-yl-oxy-phenyl)-N′-(4-methyl-phenyl)-urea,N-methyl-N-(4-pyridin-4-yl-oxy-phenyl)-N′-(4-ethyl-phenyl)-urea,N-methyl-N-(4-pyridin-4-yl-oxy-phenyl)-N′-(3-trifluoromethyl-phenyl)-urea,N-methyl-N-(4-pyridin-4-yl-oxy-phenyl)-N′-(4-n-propyl-phenyl)-urea,N-methyl-N-(4-pyridin-4-yl-oxy-phenyl)-N′-(4-methyl-phenyl)-urea,N-(4-pyridin-4-yl-oxy-phenyl)-N′-(4-bromo-3-trifluoromethyl-phenyl)-urea,N-(4-pyridin-4-yl-oxy-phenyl)-N′-(3-methoxy-5-trifluoromethyl-phenyl)-urea,N-(4-pyridin-4-ylmethyl-phenyl)-N′-(4-n-propyl-phenyl)-urea,N-(4-pyridin-4-ylmethyl-phenyl)-N′-(4-ethyl-phenyl)-urea,N-(4-pyridin-4-ylmethyl-phenyl)-N′-(4-methyl-phenyl)-urea,N-(4-pyridin-4-ylmethyl-phenyl)-N′-(3-trifluoromethyl-phenyl)-urea,N-(4-pyridin-4-yl-oxy-phenyl)acetyl-(4-ethyl-phenyl)-amide,N-(4-pyridin-4-yl-oxy-phenyl)acetyl-(4-methyl-phenyl)-amide,N-(4-pyridin-4-yl-oxy-phenyl)acetyl-(4-n-propyl-phenyl)-amide,5-(4-pyridyl-oxy)-N-(3-trifluoromethyl-phenyl)amino-carbonyl-2,3-dihydroindole,5-(4-pyridyl-oxy)-N-(3-trifluoromethyl-phenyl)amino-carbonyl-1,2,3,4-tetrahydroquinoline,N-(4-(4-Chloropyrimidin-6-yl)-oxyphenyl)-N′-(3-trifluoromethylphenyl)-urea,N-(4-pyridin-4-yl-oxyphenyl)-N′-(4-phenyl-3-trifluoromethyl-phenyl)-urea,N-(4-pyridin-4-yl-oxyphenyl)-N′-(4-(piperidin-1-yl)-3-trifluoromethyl-phenyl)-urea,N-(4-pyridin-4-yl-oxyphenyl)-N′-(4-(morpholino)-3-trifluoromethyl-phenyl)-urea,N-(4-pyridin-4-yl-oxyphenyl)-N′-(3,4,5-trimethoxy-phenyl)-urea,N-(4-pyridin-4-yl-oxyphenyl)-N′-(3-methoxy-4-phenyl-phenyl)-urea,N-(4-pyridin-4-yl-oxyphenyl)-N′-(3-methoxy-4,5-(ethylen-1,2-dioxy)-phenyl)-urea,N-(4-pyridin-4-yl-oxyphenyl)-N′-(3-methoxy-4-(2,2,2-trifluoroethoxy)-phenyl)-urea,N-(4-pyridin-4-yl-oxyphenyl)-N′-(3-methoxy-4-piperidin-1-yl-phenyl)-urea,N-(4-pyridin-4-yl-oxyphenyl)-N′-(4-piperidin-1-yl-phenyl)-urea,N-(4-[2-(4-hydroxyphenyl)-amino-pyrimidin-4-yl]-oxyphenyl-N′-(3-trifluoromethyl-phenyl)-urea,N-(4-[4-(4-sulfamoylphenyl)-amino-pyrimidin-6-yl]-oxyphenyl-N′-(3-trifluoromethyl-phenyl)-urea,N-(4-[4-(4-carbamoylphenyl)-amino-pyrimidin-6-yl]-oxyphenyl-N′-(3-trifluoromethyl-phenyl)-urea,N-(4-[4-(4-(N-2-hydroxyethylcarbamoyl)7Phenyl)-amino-pyrimidin-6-yl]-oxyphenyl-N′-(3-trifluoromethyl-phenyl)-urea,N-(4-[4-(4-hydroxyphehyl)-amino-pyrimidin-6-yl]-oxyphenyl-N′-(3-trifluoromethyl-4-(2,2,2-trifluoroethoxy)-phenyl)-urea,N-(4-(N-oxido-pyridin-4-yl)-oxyphenyl)-N′-(3-trifluoromthyl-phenyl)-urea,N-(4-(2-methoxypyridin-5-yl)-oxyphenyl)-N′-(3-trifluoromethyl-phenyl)-urea,N-(4-(2-pyridon-5-yl)-oxyphenyl)-N′-(3-trifluoromethyl-phenyl)-urea,N-[4-{(2-acetylamino)-pyridin-4-yl}-oxy]-phenyl-N′-(3-trifluoromethyl-phenyl)-urea,N-[4-(pyridin-4-yl-oxy)-2-chloro-phenyl]-N′-(3-trifluoromethyl-phenyl)-urea,N-[4-(pyridin-4-yl-oxy)-2-methyl-phenyl]-N′-(3-trifluoromethyl-phenyl)-urea,andN-(4-[4-(2-aminoethoxyphenyl)-amino-pyrimidin-6-yl]-oxyphenyl-N′-(3-trifluoromethyl-phenyl)-urea,or a pharmaceutically acceptable salt thereof.
 15. (canceled)
 16. Apharmaceutical preparation comprising a compound of the formula I or i*according to claim 7, or a tautomer thereof, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carriermaterial.
 17. A compound of the formula I or I* according to claim 7, ora tautomer thereof, or a pharmaceutically acceptable salt thereof, foruse in the treatment of the animal or human body, especially in thetreatment of a tyrosine kinase dependent disease.
 18. (canceled) 19.(canceled)
 20. A process for the preparation of a compound of theformula I according to claim 7, or a tautomer thereof, or apharmaceutically acceptable salt thereof, characterized in that (a) forthe synthesis of a compound of the formula I wherein X NR if p is 0, orif p is 2 or 3, X is nitrogen which together with (CH₂)_(p) and thebonds represented in dotted (interrupted) lines (including the atoms towhich they are bound) forms a ring, and G, Z, A, A′, Y₁, Y₂, R, R₁, R₂,R₃, R₄, R₅, m, n, p and r have the meanings as defined for a compound offormula I according to claim 7, an amino compound of the formula II

wherein X is as just defined and R₄, R₅, A, A′, Y₁, Y₂, m, n, p, r andthe bonds represented in dotted (interrupted) lines have the meanings asdefined for a compound of formula I according to claim 7, is reactedwith an isocyanate of the formula IIIO═C═N-G-Z   (III) wherein G, Z, R₁, R₂ and R₃ have the meanings asdefined for a compound of formula I according to claim 7, or (b) for thesynthesis of a compound of the formula I wherein m is O (and thus Y₂ ismissing), n is 1, Y₁ is O and G, Z, X, R₁, R₂, R₃, R4, R₅, A, A′, p andr have the meanings as defined for a compound of formula I according toclaim 7, a hydroxy compound of the formula IV

wherein G, Z, X, R₁, R₂, R₃, R₅, p and the bonds represented in dotted(interrupted) lines have the meanings as defined for a compound offormula I according to claim 7, is etherified with a halo compound ofthe formula V

wherein R₄ and r have the meanings as defined for a compound of formulaI according to claim 7 and Hal is halo, especially chloro, or (c) forthe synthesis of a compound of the formula I wherein p is zero, X isCHK, especially CH₂, and G, Z, K, Y₁, Y₂, R₁, R₂, R₃, R₄, R₅, A, A′, m,n and r have the meanings as defined for a compound of formula Iaccording to claim 7, a carboxyl compound of the formula VI

wherein K is lower alkyl or preferably hydrogen and A, A′, Y₁, Y₂, R₄,R₅, m, n and r have the meanings as defined for a compound of formula Iaccording to claim 7, or a reactive derivative thereof, is condensedwith an amino compound of the formula VIIH₂N-G-Z   (VII) wherein G, Z, R₁, R₂ and R₃ have the meanings as definedfor a compound of formula I according to claim 7, or (d) for thesynthesis of a compound of the formula I wherein X is NH, p is zero andG, Z, A, A′, Y₁, Y₂, R₁, R₂, R₃, R₄, R₅, m, n and r have the meanings asdefined for a compound of formula I according to claim 7, an isocyanateof the formula VIII

wherein R₄, A, A′, Y₁, Y₂, m, n, r and R₅ have the meanings as definedfor a compound of formula I according to claim 7, is reacted with anamino compound of the formula IXH₂N-GZ   (IX) wherein G, Z, R₁, R₂ and R₃ have the meanings as definedfor a compound of formula I according to claim 7, and, if desired, afterreaction (a), (b), (c) or (d) an obtainable compound of formula I istransformed into a different compound of formula I, a salt of anobtainable compound of formula I is transformed into the free compoundor a different salt, or an obtainable free compound of formula I istransformed into a salt; and/or an obtainable mixture of isomers ofcompounds of formula I is separated into the individual isomers; wherefor all reactions mentioned functional groups in the starting materialsthat shall not take part in the reaction are, if required, present inprotected form by readily removable protecting groups, and anyprotecting groups are subsequently removed.
 21. A compound of theformula I*

wherein A is CH, N or N→O and A′ is N or N→O, with the proviso that notmore than one of A and A′ can be N→O; n is 1 or 2; m is 0, 1 or 2; p is1 or 3; r is 0 to 5; X is NR if p is 0, wherein R is hydrogen or anorganic moiety, or if p is 2 or 3, X is nitrogen which together with(CH₂)_(p) and the bonds represented in dotted (interrupted) lines(including the atoms to which they are bound) forms a ring, or X is CHKwherein K is lower alkyl or hydrogen and p is zero, with the provisothat the bonds represented in dotted lines, if p is zero, are absent; Y₁is O, S or CH₂; Y₂ is O, S or NH; with the proviso that(Y₁)_(n)—(Y₂)_(m) does not include O—O, S—S, NH—O, NH—S or S—O groups;each of R₁, R₂, R₃ and R₅, independently of the others, is hydrogen oran inorganic or organic moiety or any two of them together form a loweralkylene-dioxy bridge bound via the oxygen atoms, and the remaining oneof these moieties is hydrogen or an inorganic or organic moiety; and R₄(if present, that is, if r is not zero) is an inorganic or organicmoiety; or a tautomer thereof; or a pharmaceutically acceptable saltthereof.